Michael Mendoza, MD, MPH, MS, FAAFP

The opioid crisis has brought added scrutiny to opioid prescribing, particularly to health care providers, whom many blame for the genesis of the opioid overdose epidemic. Family physicians are acutely aware of these complexities: By sheer volume, family physicians prescribe more opioid analgesics than any other subspecialist.¹

Overwhelmed by opioid prescriptions

Because of a complexity of factors (notably, the influence of the US pharmaceutical industry), the quantity of opioid prescriptions has risen substantially—enough so that, in 2010, opioids were prescribed in great enough quantity to medicate every American around the clock for a month.² Among people who began abusing opioids in the 2000s, 75% reported that their first opioid was a prescription drug; this is a shift from prior decades, when heroin was the gateway to opioid addiction.³ As the reality of the size of the opioid problem sunk in, many were hopeful that the epidemic would reverse itself as quickly as it began if the medical community would simply prescribe fewer opioids.

©Stuart Bradford

Since 2010, the opioid overdose fatality rate has risen dramatically, even though prescription opioid overdose mortality has leveled off, or even declined. ² One explanation for this paradox? As availability of prescription opioids declined, people suffering from an underlying opioid use disorder (OUD) turned instead first to heroin, then later to potent fentanyl analogues to fuel their addiction. In most communities, the prevalence of fentanyl analogues—alone or more commonly mixed with other opioids—has driven the staggering rise in opioid-related fatalities in recent years.

No question: Prescription opioids played a critical role in the origins of this epidemic, but just withdrawing prescriptions will not result in marked reduction in the epidemic. This quandary is no more apparent than in primary care, where the considerable risk of continuing opioids—especially at high dosages—must be weighed against the potential risks of discontinuation. Adding to this dilemma are lack of access to treatment for patients with an OUD and the continued stigma and misunderstanding of substance use disorders.

In this article, we describe the challenges of long-term opioid use and review necessary protocols and precautions for maintaining or tapering an opioid regimen in patients who suffer chronic pain.

Managing chronic pain is fraught with complexity

Chronic pain is both real and a disease in its own right. Although definitions of chronic pain vary, pain that lasts > 3 months or past the duration of normal tissue healing is typically considered chronic.⁴ Approximations of prevalence vary, but in 1 study that examined a representative sample, it was estimated that 14.6% of US adults experience chronic pain.⁵

Patients who report symptoms or a history of chronic pain can elicit negative reactions from physicians—stemming from our biases, which can inadvertently provoke emotions on our part.⁶ Unflattering portrayals of patients in the media can further fuel unwarranted biases and prejudices.⁷

Continue to: Preventing, assessing, and treating...

 

Preventing, assessing, and treating chronic pain can be difficult, at the level of both the individual physician and the larger system of care, even without adding in complications of the opioid epidemic. For racial and ethnic minority groups, women, older people, and people with cognitive impairment or cancer, pain can be underrecognized and go inadequately treated.

Among people who began abusing opioids in the 2000s, 75% said that their first opioid was a prescription drug; in prior decades, heroin was the gateway to opioid addiction.

Chronic pain itself has clinical, psychological, and social consequences and is associated with limitations in activity, work productivity, quality of life, and stigma.⁸ Treatment of chronic pain—with opioids or other modalities—remains an important component of patient-centered primary care. Interestingly, however, many patients struggling through chronic pain report that efforts to curb the opioid epidemic have inadvertently led to lower-quality pain management and, therefore, understandable concern among patients whose chronic pain is well managed with opioid pain medications.^9,10

When is it appropriate to continue opioids for chronic pain?

Apart from the treatment of active cancer, palliative care, and end-of-life care, the appropriate use of opioids for chronic and acute pain has become clouded in recent years. To assist with this problem, the Centers for Disease Control and Prevention issued guidelines in 2016 for primary care physicians who are faced with this clinical dilemma.¹¹ The guidelines (1) address circumstances in which it is safe to consider opioid prescribing and (2) provide ongoing reassessment of indications for chronic opioid prescribing within the context of potential risk to the patient and society. Because appropriate use of opioids has grown murky, nonpharmacotherapeutic management and nonopioid pharmacotherapy are preferred for chronic pain.

The therapeutic window— between safe dosages and those that could lead to respiratory depression or overdose— is narrow for older patients.

Plan ahead. Establish goals of treatment that focus on both pain and function when starting opioid therapy. This will facilitate decision-making when it comes time to continue—or discontinue—opioids down the road. Opioids should be prescribed at the lowest effective dosage; ongoing reassessment of benefit should be made, and particular caution should be exercised, if the daily opioid dosage reaches ≥ 50 morphine milligram equivalents (MME) and especially as the dosage approaches ≥ 90 MME/d. Prescribers should ensure that patients are educated about known risks and the limited evidence of benefit of opioid therapy.

An age-related concern. Special consideration is warranted in older patients, who might have reduced renal function even in the absence of renal disease; this can lead to a reduction in clearance of pain medication. Because of that increased risk of drug accumulation, the therapeutic window—between safe dosages and those that could lead to respiratory depression or overdose—is narrow for these patients.¹¹

Continue to: Use in pregnancy

 

Use in pregnancy. Treatment with opioid medication in pregnancy warrants special consideration. In general, it’s wise to avoid opioid use in pregnant women because data on long- and short-term safety are limited.¹² In 2015, the US Food and Drug Administration issued a safety announcement that further investigation is needed to determine whether the fetus is at increased risk of a neural tube defect related to opioid exposure during the first trimester.¹³ In women with an OUD, both methadone and buprenorphine are safe to use. Buprenorphine is associated with slightly better outcomes for neonatal abstinence syndrome and length of hospital stay.¹⁴

Ongoing monitoring of risk. Periodically assessing risk factors for opioid-related harm during continuation of opioid treatment is important. Tools such as the Opioid Risk Tool (ORT) or the Screener and Opioid Assessment for Patients with Pain-Revised, or SOAPP-R, can be used to evaluate the risk of misuse in adults who are prescribed opioids for chronic pain,¹⁵ although the evidence for utilizing these tools is inconclusive.¹¹

Offering naloxone should be considered when factors that increase the risk of opioid overdose are present, such as a history of substance use disorder, a daily opioid dosage > 50 MME, concurrent use of benzodiazepines, and medical comorbidities that increase the risk of overdose (eg, sleep apnea, pulmonary disease, heart failure).¹⁶ Prescribers should review prescription drug monitoring program data, when available, to assess treatment adherence and to obtain a collateral history that might suggest abuse or diversion. Urine drug testing can be a useful adjunct to ongoing therapy—again, to assess treatment adherence and look for evidence of other substance use disorders.

Watchfulness for misuse and OUD. Opioid misuse—the nontherapeutic use of opioids—includes taking opioids in amounts other than prescribed, for indications other than prescribed, and administering by alternative routes other than prescribed (eg, crushing and snorting, rather than ingesting). The presence of opioid misuse does not always signify OUD. However, The Diagnostic and Statistical Manual of Mental Disorders, 5th ed.,¹⁷ defines OUD as out-of-control use; devoting increasing mental and physical resources to obtaining, using, and recovering from substances; and continued use despite adverse consequences.

Behaviors that increase the risk of, and might signal, opioid misuse and OUD include¹⁸

• seeking early refills
• obtaining opioids from the emergency room
• using medications prescribed to others
• using opioids to treat symptoms other than pain, such as anxiety or insomnia
• “doctor-shopping.”

Continue to: Furthermore...

 

Furthermore, psychiatric comorbidities,¹⁹ a personal or family history of substance use disorder,²⁰ and a preadolescent history of sexual abuse²¹ are associated with a higher risk of a substance use disorder.

If OUD is identified, remain nonjudgmental and acknowledge that addiction is a chronic disease. Assumptions about a patient’s character or morality have no place in the appropriate management of OUD; remain mindful of your own implicit biases.

When is it appropriateto start an opioid taper?

The decision to taper opioids is difficult and can provoke anxiety for both prescriber and patient. Complicating matters is that there is insufficient evidence to evaluate opioid dosage-reduction interventions for patients with chronic noncancer pain.²²

Safety concerns. Even in patients who are taking opioids as prescribed and for whom no red flags have been raised, the long-term safety of high-dosage opioids remains unclear. There is no “safe” dosage of opioids; however, evidence is clear that the risk of death from overdose increases with dosage. Compared with patients taking a dosage anywhere from 1 to 20 MME/d, those taking 50 to 99 MME/d have a 3.7-fold increased risk of overdose; patients taking ≥ 100 MME/d had an 8.9-fold increased risk.²³ Patients for whom concomitant benzodiazepines are prescribed are also at higher risk of overdose and death. In studies of opioid overdose deaths, there was evidence of concurrent benzodiazepine use in 31% to 61% of cases.¹¹

Inadequate analgesia. Given the well-established risk of drug tolerance, the inability to achieve or maintain pain relief or functional improvement can still occur—even when the opioid dosage is escalated reasonably. It might be prudent in that situation to taper opioids while also considering alternative modalities, including ones that were deferred previously.

Continue to: Intolerable adverse effects

 

Intolerable adverse effects. Adverse effects are common. Constipation has a reported prevalence of 15% to 90% among patients on long-term opioid treatment.²⁴ Short-term, mild constipation is often manageable; long-term opioid use, however, can produce constipation refractory to bowel regimens and, in rare cases, lead to bowel obstruction, perforation, and even death. Other adverse effects include²⁵

• sedation and drowsiness
• impaired memory or concentration
• mood changes
• dry mouth
• abdominal pain and nausea
• sexual dysfunction.

When these effects limit the tolerability of treatment, tapering might be indicated.

How are opioids tapered?

There is no definitive evidence of an optimal rate of taper or frequency of follow-up. Most guidelines suggest tapering opioids at 10% of the dosage each week; patients who have been taking opioids for many years, however, might require a slower taper (eg, a dosage decrease of 5%-20% every 2-4 weeks).¹¹

Psychosocial support and maximizing nonopioid pain management techniques are critical to successful opioid tapering. When tapering is part of a comprehensive pain and rehabilitative plan, patients might find their symptoms alleviated.²⁶ Given the potential risks in patients taking both short- and long-acting opioids, tapering the long-acting opioid should be the initial priority.

Psychiatric comorbidities, a personal or family history of substance use disorder, and a preadolescent history of sexual abuse are associated with a higher risk of a substance use disorder.

A more rapid taper—eg, a 20% reduction each week or even abrupt discontinuation of opioids—might be necessary if diversion is suspected or if there is concern that continued use of the medication presents high risk. In such cases, consultation with an addiction medicine specialist can be helpful—to assess whether medication-assisted therapy for OUD would be appropriate and how to support patients who are having withdrawal symptoms.

Continue to: For all patients...

 

For all patients, frequent follow-up visits with their primary care clinician, as well as referrals to mental health, physical therapy, and pain or rehabilitation services, can promote a successful taper. It is advised that, before beginning a taper, a treatment plan should be written out with the patient so that expectations are shared by physician and patient for the goals of the taper, the speed of dosage decreases, and the frequency of follow-up after each dosage change. At each follow-up visit, education regarding self-management and individualized recommendations for psychosocial support, mental health services, and substance use disorder services should be updated.

Assessing risk when tapering chronic opioid therapy

The goals of tapering should be to (1) reduce adverse effects of treatment and (2) mitigate short- and long-term risks.

Three short-term risks

Unmasking OUD. Tapering prescribed opioids, or even just discussing tapering, can unmask OUD in some patients. Follow-up visits during the tapering schedule should include frequent screening for OUD. If OUD is diagnosed, we recommend beginning medication-assisted treatment or referring the patient to a substance use treatment center. There is strong evidence of the safety and efficacy of medication-assisted treatment, even with a coexisting chronic pain disorder.²⁷

Withdrawal syndrome. Opioid withdrawal syndrome is characterized by signs and symptoms of sympathetic stimulation, resulting from decreased sympathetic blockade by opioids (TABLE).²⁸ (See “Changes in the locus ceruleus lead to withdrawal.”²⁹) Symptoms start 2 to 3 half-lives after the last dose of opioid. Oxycodone, for example, has a half-life of 3 to 4 hours; withdrawal symptoms should therefore be anticipated in 6 to 12 hours. Because mixing opioids is commonplace, it can be difficult to predict exactly when withdrawal symptoms will begin. Patients are often most helpful in predicting the onset and severity of withdrawal symptoms.

Withdrawal can be measured using any of a number of validated tools, including

• the Subjective Opiate Withdrawal Scale, or SOWS³⁰ (FIGURE 1), which utilizes a patient self-report
• the Clinical Opiate Withdrawal Scale, or COWS³¹ (FIGURE 2), which relies on assessment made by the physician.

Continue to: Although withdrawal...

 

Although withdrawal is generally not considered life-threatening in patients without significant comorbidities, do not underestimate the severity of withdrawal symptoms. Often, the desire to avoid these intense symptoms drives patients with OUD to continue to overuse.

Increased pain. Patients might fear that pain will become worse if opioids are tapered. Although it is important to acknowledge this fear, studies of patients undergoing a long-term opioid taper report improvements in function without loss of adequate pain control; some even report that pain control improves.³²

Three long-term risks

Relapse. The most dangerous risk of tapering opioids is use of illicit opioids, a danger made worse by the increasing presence of highly lethal synthetic fentanyl analogues in the community. Risk factors for relapse following a full taper include the presence of depressive symptoms at initiation of tapering and higher pain scores at initiation and conclusion of the taper.³³ Having low pain at the end of an opioid taper, on the other hand, is predictive of long-term abstinence from opioids.³²

Declining function. As is the case while prescribing opioids for pain, maintenance of function remains a priority when tapering opioids. Function can be difficult to assess, given the many variables that can influence an individual’s function. Psychosocial factors, such as coping strategies and mood, strongly influence function; so do psychiatric morbidities, which are more prevalent in patients with chronic pain and disability, compared with the general population.³⁴

Medicolegal matters. Although difficult to characterize, medicolegal risk is an inevitable consideration when tapering opioids:

• In a study of closed malpractice claims involving all medical specialties, narcotic pain medications were the most common drug class involved, representing 1% of claims.³⁵
• In a study of closed malpractice claims involving pain medicine specialists, 3% were related to medication management. Most claims arose following death from opioid overdose.³⁶

Continue to: What else is needed in this area of practice?

 

 

What else is needed in this area of practice?

Increasingly, family physicians face the inherent tension of wanting to provide patient-centered, compassionate care for patients in pain while being mindful of opioid prescription stewardship. To support their work and help allay this tension, clinical research on this topic in the future should focus on

• new options for nonopioid pharmacotherapy for pain
• best practices for using opioids in noncancer chronic pain.

In addition, health care systems can help—by providing insurance coverage of nonpharmacotherapeutic options for treating pain.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 111 Westfall Road, Room 952, Rochester, NY 14620; MichaelMendoza@ monroecounty.gov

The opioid crisis has brought added scrutiny to opioid prescribing, particularly to health care providers, whom many blame for the genesis of the opioid overdose epidemic. Family physicians are acutely aware of these complexities: By sheer volume, family physicians prescribe more opioid analgesics than any other subspecialist.¹

Overwhelmed by opioid prescriptions

Because of a complexity of factors (notably, the influence of the US pharmaceutical industry), the quantity of opioid prescriptions has risen substantially—enough so that, in 2010, opioids were prescribed in great enough quantity to medicate every American around the clock for a month.² Among people who began abusing opioids in the 2000s, 75% reported that their first opioid was a prescription drug; this is a shift from prior decades, when heroin was the gateway to opioid addiction.³ As the reality of the size of the opioid problem sunk in, many were hopeful that the epidemic would reverse itself as quickly as it began if the medical community would simply prescribe fewer opioids.

©Stuart Bradford

Since 2010, the opioid overdose fatality rate has risen dramatically, even though prescription opioid overdose mortality has leveled off, or even declined. ² One explanation for this paradox? As availability of prescription opioids declined, people suffering from an underlying opioid use disorder (OUD) turned instead first to heroin, then later to potent fentanyl analogues to fuel their addiction. In most communities, the prevalence of fentanyl analogues—alone or more commonly mixed with other opioids—has driven the staggering rise in opioid-related fatalities in recent years.

No question: Prescription opioids played a critical role in the origins of this epidemic, but just withdrawing prescriptions will not result in marked reduction in the epidemic. This quandary is no more apparent than in primary care, where the considerable risk of continuing opioids—especially at high dosages—must be weighed against the potential risks of discontinuation. Adding to this dilemma are lack of access to treatment for patients with an OUD and the continued stigma and misunderstanding of substance use disorders.

In this article, we describe the challenges of long-term opioid use and review necessary protocols and precautions for maintaining or tapering an opioid regimen in patients who suffer chronic pain.

Managing chronic pain is fraught with complexity

Chronic pain is both real and a disease in its own right. Although definitions of chronic pain vary, pain that lasts > 3 months or past the duration of normal tissue healing is typically considered chronic.⁴ Approximations of prevalence vary, but in 1 study that examined a representative sample, it was estimated that 14.6% of US adults experience chronic pain.⁵

Patients who report symptoms or a history of chronic pain can elicit negative reactions from physicians—stemming from our biases, which can inadvertently provoke emotions on our part.⁶ Unflattering portrayals of patients in the media can further fuel unwarranted biases and prejudices.⁷

Continue to: Preventing, assessing, and treating...

 

Preventing, assessing, and treating chronic pain can be difficult, at the level of both the individual physician and the larger system of care, even without adding in complications of the opioid epidemic. For racial and ethnic minority groups, women, older people, and people with cognitive impairment or cancer, pain can be underrecognized and go inadequately treated.

Among people who began abusing opioids in the 2000s, 75% said that their first opioid was a prescription drug; in prior decades, heroin was the gateway to opioid addiction.

Chronic pain itself has clinical, psychological, and social consequences and is associated with limitations in activity, work productivity, quality of life, and stigma.⁸ Treatment of chronic pain—with opioids or other modalities—remains an important component of patient-centered primary care. Interestingly, however, many patients struggling through chronic pain report that efforts to curb the opioid epidemic have inadvertently led to lower-quality pain management and, therefore, understandable concern among patients whose chronic pain is well managed with opioid pain medications.^9,10

When is it appropriate to continue opioids for chronic pain?

Apart from the treatment of active cancer, palliative care, and end-of-life care, the appropriate use of opioids for chronic and acute pain has become clouded in recent years. To assist with this problem, the Centers for Disease Control and Prevention issued guidelines in 2016 for primary care physicians who are faced with this clinical dilemma.¹¹ The guidelines (1) address circumstances in which it is safe to consider opioid prescribing and (2) provide ongoing reassessment of indications for chronic opioid prescribing within the context of potential risk to the patient and society. Because appropriate use of opioids has grown murky, nonpharmacotherapeutic management and nonopioid pharmacotherapy are preferred for chronic pain.

The therapeutic window— between safe dosages and those that could lead to respiratory depression or overdose— is narrow for older patients.

Plan ahead. Establish goals of treatment that focus on both pain and function when starting opioid therapy. This will facilitate decision-making when it comes time to continue—or discontinue—opioids down the road. Opioids should be prescribed at the lowest effective dosage; ongoing reassessment of benefit should be made, and particular caution should be exercised, if the daily opioid dosage reaches ≥ 50 morphine milligram equivalents (MME) and especially as the dosage approaches ≥ 90 MME/d. Prescribers should ensure that patients are educated about known risks and the limited evidence of benefit of opioid therapy.

An age-related concern. Special consideration is warranted in older patients, who might have reduced renal function even in the absence of renal disease; this can lead to a reduction in clearance of pain medication. Because of that increased risk of drug accumulation, the therapeutic window—between safe dosages and those that could lead to respiratory depression or overdose—is narrow for these patients.¹¹

Continue to: Use in pregnancy

 

Use in pregnancy. Treatment with opioid medication in pregnancy warrants special consideration. In general, it’s wise to avoid opioid use in pregnant women because data on long- and short-term safety are limited.¹² In 2015, the US Food and Drug Administration issued a safety announcement that further investigation is needed to determine whether the fetus is at increased risk of a neural tube defect related to opioid exposure during the first trimester.¹³ In women with an OUD, both methadone and buprenorphine are safe to use. Buprenorphine is associated with slightly better outcomes for neonatal abstinence syndrome and length of hospital stay.¹⁴

Ongoing monitoring of risk. Periodically assessing risk factors for opioid-related harm during continuation of opioid treatment is important. Tools such as the Opioid Risk Tool (ORT) or the Screener and Opioid Assessment for Patients with Pain-Revised, or SOAPP-R, can be used to evaluate the risk of misuse in adults who are prescribed opioids for chronic pain,¹⁵ although the evidence for utilizing these tools is inconclusive.¹¹

Offering naloxone should be considered when factors that increase the risk of opioid overdose are present, such as a history of substance use disorder, a daily opioid dosage > 50 MME, concurrent use of benzodiazepines, and medical comorbidities that increase the risk of overdose (eg, sleep apnea, pulmonary disease, heart failure).¹⁶ Prescribers should review prescription drug monitoring program data, when available, to assess treatment adherence and to obtain a collateral history that might suggest abuse or diversion. Urine drug testing can be a useful adjunct to ongoing therapy—again, to assess treatment adherence and look for evidence of other substance use disorders.

Watchfulness for misuse and OUD. Opioid misuse—the nontherapeutic use of opioids—includes taking opioids in amounts other than prescribed, for indications other than prescribed, and administering by alternative routes other than prescribed (eg, crushing and snorting, rather than ingesting). The presence of opioid misuse does not always signify OUD. However, The Diagnostic and Statistical Manual of Mental Disorders, 5th ed.,¹⁷ defines OUD as out-of-control use; devoting increasing mental and physical resources to obtaining, using, and recovering from substances; and continued use despite adverse consequences.

Behaviors that increase the risk of, and might signal, opioid misuse and OUD include¹⁸

• seeking early refills
• obtaining opioids from the emergency room
• using medications prescribed to others
• using opioids to treat symptoms other than pain, such as anxiety or insomnia
• “doctor-shopping.”

Continue to: Furthermore...

 

Furthermore, psychiatric comorbidities,¹⁹ a personal or family history of substance use disorder,²⁰ and a preadolescent history of sexual abuse²¹ are associated with a higher risk of a substance use disorder.

If OUD is identified, remain nonjudgmental and acknowledge that addiction is a chronic disease. Assumptions about a patient’s character or morality have no place in the appropriate management of OUD; remain mindful of your own implicit biases.

When is it appropriateto start an opioid taper?

The decision to taper opioids is difficult and can provoke anxiety for both prescriber and patient. Complicating matters is that there is insufficient evidence to evaluate opioid dosage-reduction interventions for patients with chronic noncancer pain.²²

Safety concerns. Even in patients who are taking opioids as prescribed and for whom no red flags have been raised, the long-term safety of high-dosage opioids remains unclear. There is no “safe” dosage of opioids; however, evidence is clear that the risk of death from overdose increases with dosage. Compared with patients taking a dosage anywhere from 1 to 20 MME/d, those taking 50 to 99 MME/d have a 3.7-fold increased risk of overdose; patients taking ≥ 100 MME/d had an 8.9-fold increased risk.²³ Patients for whom concomitant benzodiazepines are prescribed are also at higher risk of overdose and death. In studies of opioid overdose deaths, there was evidence of concurrent benzodiazepine use in 31% to 61% of cases.¹¹

Inadequate analgesia. Given the well-established risk of drug tolerance, the inability to achieve or maintain pain relief or functional improvement can still occur—even when the opioid dosage is escalated reasonably. It might be prudent in that situation to taper opioids while also considering alternative modalities, including ones that were deferred previously.

Continue to: Intolerable adverse effects

 

Intolerable adverse effects. Adverse effects are common. Constipation has a reported prevalence of 15% to 90% among patients on long-term opioid treatment.²⁴ Short-term, mild constipation is often manageable; long-term opioid use, however, can produce constipation refractory to bowel regimens and, in rare cases, lead to bowel obstruction, perforation, and even death. Other adverse effects include²⁵

• sedation and drowsiness
• impaired memory or concentration
• mood changes
• dry mouth
• abdominal pain and nausea
• sexual dysfunction.

When these effects limit the tolerability of treatment, tapering might be indicated.

How are opioids tapered?

There is no definitive evidence of an optimal rate of taper or frequency of follow-up. Most guidelines suggest tapering opioids at 10% of the dosage each week; patients who have been taking opioids for many years, however, might require a slower taper (eg, a dosage decrease of 5%-20% every 2-4 weeks).¹¹

Psychosocial support and maximizing nonopioid pain management techniques are critical to successful opioid tapering. When tapering is part of a comprehensive pain and rehabilitative plan, patients might find their symptoms alleviated.²⁶ Given the potential risks in patients taking both short- and long-acting opioids, tapering the long-acting opioid should be the initial priority.

Psychiatric comorbidities, a personal or family history of substance use disorder, and a preadolescent history of sexual abuse are associated with a higher risk of a substance use disorder.

A more rapid taper—eg, a 20% reduction each week or even abrupt discontinuation of opioids—might be necessary if diversion is suspected or if there is concern that continued use of the medication presents high risk. In such cases, consultation with an addiction medicine specialist can be helpful—to assess whether medication-assisted therapy for OUD would be appropriate and how to support patients who are having withdrawal symptoms.

Continue to: For all patients...

 

For all patients, frequent follow-up visits with their primary care clinician, as well as referrals to mental health, physical therapy, and pain or rehabilitation services, can promote a successful taper. It is advised that, before beginning a taper, a treatment plan should be written out with the patient so that expectations are shared by physician and patient for the goals of the taper, the speed of dosage decreases, and the frequency of follow-up after each dosage change. At each follow-up visit, education regarding self-management and individualized recommendations for psychosocial support, mental health services, and substance use disorder services should be updated.

Assessing risk when tapering chronic opioid therapy

The goals of tapering should be to (1) reduce adverse effects of treatment and (2) mitigate short- and long-term risks.

Three short-term risks

Unmasking OUD. Tapering prescribed opioids, or even just discussing tapering, can unmask OUD in some patients. Follow-up visits during the tapering schedule should include frequent screening for OUD. If OUD is diagnosed, we recommend beginning medication-assisted treatment or referring the patient to a substance use treatment center. There is strong evidence of the safety and efficacy of medication-assisted treatment, even with a coexisting chronic pain disorder.²⁷

Withdrawal syndrome. Opioid withdrawal syndrome is characterized by signs and symptoms of sympathetic stimulation, resulting from decreased sympathetic blockade by opioids (TABLE).²⁸ (See “Changes in the locus ceruleus lead to withdrawal.”²⁹) Symptoms start 2 to 3 half-lives after the last dose of opioid. Oxycodone, for example, has a half-life of 3 to 4 hours; withdrawal symptoms should therefore be anticipated in 6 to 12 hours. Because mixing opioids is commonplace, it can be difficult to predict exactly when withdrawal symptoms will begin. Patients are often most helpful in predicting the onset and severity of withdrawal symptoms.

Withdrawal can be measured using any of a number of validated tools, including

• the Subjective Opiate Withdrawal Scale, or SOWS³⁰ (FIGURE 1), which utilizes a patient self-report
• the Clinical Opiate Withdrawal Scale, or COWS³¹ (FIGURE 2), which relies on assessment made by the physician.

Continue to: Although withdrawal...

 

Although withdrawal is generally not considered life-threatening in patients without significant comorbidities, do not underestimate the severity of withdrawal symptoms. Often, the desire to avoid these intense symptoms drives patients with OUD to continue to overuse.

Increased pain. Patients might fear that pain will become worse if opioids are tapered. Although it is important to acknowledge this fear, studies of patients undergoing a long-term opioid taper report improvements in function without loss of adequate pain control; some even report that pain control improves.³²

Three long-term risks

Relapse. The most dangerous risk of tapering opioids is use of illicit opioids, a danger made worse by the increasing presence of highly lethal synthetic fentanyl analogues in the community. Risk factors for relapse following a full taper include the presence of depressive symptoms at initiation of tapering and higher pain scores at initiation and conclusion of the taper.³³ Having low pain at the end of an opioid taper, on the other hand, is predictive of long-term abstinence from opioids.³²

Declining function. As is the case while prescribing opioids for pain, maintenance of function remains a priority when tapering opioids. Function can be difficult to assess, given the many variables that can influence an individual’s function. Psychosocial factors, such as coping strategies and mood, strongly influence function; so do psychiatric morbidities, which are more prevalent in patients with chronic pain and disability, compared with the general population.³⁴

Medicolegal matters. Although difficult to characterize, medicolegal risk is an inevitable consideration when tapering opioids:

• In a study of closed malpractice claims involving all medical specialties, narcotic pain medications were the most common drug class involved, representing 1% of claims.³⁵
• In a study of closed malpractice claims involving pain medicine specialists, 3% were related to medication management. Most claims arose following death from opioid overdose.³⁶

Continue to: What else is needed in this area of practice?

 

 

What else is needed in this area of practice?

Increasingly, family physicians face the inherent tension of wanting to provide patient-centered, compassionate care for patients in pain while being mindful of opioid prescription stewardship. To support their work and help allay this tension, clinical research on this topic in the future should focus on

• new options for nonopioid pharmacotherapy for pain
• best practices for using opioids in noncancer chronic pain.

In addition, health care systems can help—by providing insurance coverage of nonpharmacotherapeutic options for treating pain.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 111 Westfall Road, Room 952, Rochester, NY 14620; MichaelMendoza@ monroecounty.gov

The opioid crisis has brought added scrutiny to opioid prescribing, particularly to health care providers, whom many blame for the genesis of the opioid overdose epidemic. Family physicians are acutely aware of these complexities: By sheer volume, family physicians prescribe more opioid analgesics than any other subspecialist.¹

Overwhelmed by opioid prescriptions

Because of a complexity of factors (notably, the influence of the US pharmaceutical industry), the quantity of opioid prescriptions has risen substantially—enough so that, in 2010, opioids were prescribed in great enough quantity to medicate every American around the clock for a month.² Among people who began abusing opioids in the 2000s, 75% reported that their first opioid was a prescription drug; this is a shift from prior decades, when heroin was the gateway to opioid addiction.³ As the reality of the size of the opioid problem sunk in, many were hopeful that the epidemic would reverse itself as quickly as it began if the medical community would simply prescribe fewer opioids.

©Stuart Bradford

Since 2010, the opioid overdose fatality rate has risen dramatically, even though prescription opioid overdose mortality has leveled off, or even declined. ² One explanation for this paradox? As availability of prescription opioids declined, people suffering from an underlying opioid use disorder (OUD) turned instead first to heroin, then later to potent fentanyl analogues to fuel their addiction. In most communities, the prevalence of fentanyl analogues—alone or more commonly mixed with other opioids—has driven the staggering rise in opioid-related fatalities in recent years.

No question: Prescription opioids played a critical role in the origins of this epidemic, but just withdrawing prescriptions will not result in marked reduction in the epidemic. This quandary is no more apparent than in primary care, where the considerable risk of continuing opioids—especially at high dosages—must be weighed against the potential risks of discontinuation. Adding to this dilemma are lack of access to treatment for patients with an OUD and the continued stigma and misunderstanding of substance use disorders.

In this article, we describe the challenges of long-term opioid use and review necessary protocols and precautions for maintaining or tapering an opioid regimen in patients who suffer chronic pain.

Managing chronic pain is fraught with complexity

Chronic pain is both real and a disease in its own right. Although definitions of chronic pain vary, pain that lasts > 3 months or past the duration of normal tissue healing is typically considered chronic.⁴ Approximations of prevalence vary, but in 1 study that examined a representative sample, it was estimated that 14.6% of US adults experience chronic pain.⁵

Patients who report symptoms or a history of chronic pain can elicit negative reactions from physicians—stemming from our biases, which can inadvertently provoke emotions on our part.⁶ Unflattering portrayals of patients in the media can further fuel unwarranted biases and prejudices.⁷

Continue to: Preventing, assessing, and treating...

 

Preventing, assessing, and treating chronic pain can be difficult, at the level of both the individual physician and the larger system of care, even without adding in complications of the opioid epidemic. For racial and ethnic minority groups, women, older people, and people with cognitive impairment or cancer, pain can be underrecognized and go inadequately treated.

Among people who began abusing opioids in the 2000s, 75% said that their first opioid was a prescription drug; in prior decades, heroin was the gateway to opioid addiction.

Chronic pain itself has clinical, psychological, and social consequences and is associated with limitations in activity, work productivity, quality of life, and stigma.⁸ Treatment of chronic pain—with opioids or other modalities—remains an important component of patient-centered primary care. Interestingly, however, many patients struggling through chronic pain report that efforts to curb the opioid epidemic have inadvertently led to lower-quality pain management and, therefore, understandable concern among patients whose chronic pain is well managed with opioid pain medications.^9,10

When is it appropriate to continue opioids for chronic pain?

Apart from the treatment of active cancer, palliative care, and end-of-life care, the appropriate use of opioids for chronic and acute pain has become clouded in recent years. To assist with this problem, the Centers for Disease Control and Prevention issued guidelines in 2016 for primary care physicians who are faced with this clinical dilemma.¹¹ The guidelines (1) address circumstances in which it is safe to consider opioid prescribing and (2) provide ongoing reassessment of indications for chronic opioid prescribing within the context of potential risk to the patient and society. Because appropriate use of opioids has grown murky, nonpharmacotherapeutic management and nonopioid pharmacotherapy are preferred for chronic pain.

The therapeutic window— between safe dosages and those that could lead to respiratory depression or overdose— is narrow for older patients.

Plan ahead. Establish goals of treatment that focus on both pain and function when starting opioid therapy. This will facilitate decision-making when it comes time to continue—or discontinue—opioids down the road. Opioids should be prescribed at the lowest effective dosage; ongoing reassessment of benefit should be made, and particular caution should be exercised, if the daily opioid dosage reaches ≥ 50 morphine milligram equivalents (MME) and especially as the dosage approaches ≥ 90 MME/d. Prescribers should ensure that patients are educated about known risks and the limited evidence of benefit of opioid therapy.

An age-related concern. Special consideration is warranted in older patients, who might have reduced renal function even in the absence of renal disease; this can lead to a reduction in clearance of pain medication. Because of that increased risk of drug accumulation, the therapeutic window—between safe dosages and those that could lead to respiratory depression or overdose—is narrow for these patients.¹¹

Continue to: Use in pregnancy

 

Use in pregnancy. Treatment with opioid medication in pregnancy warrants special consideration. In general, it’s wise to avoid opioid use in pregnant women because data on long- and short-term safety are limited.¹² In 2015, the US Food and Drug Administration issued a safety announcement that further investigation is needed to determine whether the fetus is at increased risk of a neural tube defect related to opioid exposure during the first trimester.¹³ In women with an OUD, both methadone and buprenorphine are safe to use. Buprenorphine is associated with slightly better outcomes for neonatal abstinence syndrome and length of hospital stay.¹⁴

Ongoing monitoring of risk. Periodically assessing risk factors for opioid-related harm during continuation of opioid treatment is important. Tools such as the Opioid Risk Tool (ORT) or the Screener and Opioid Assessment for Patients with Pain-Revised, or SOAPP-R, can be used to evaluate the risk of misuse in adults who are prescribed opioids for chronic pain,¹⁵ although the evidence for utilizing these tools is inconclusive.¹¹

Offering naloxone should be considered when factors that increase the risk of opioid overdose are present, such as a history of substance use disorder, a daily opioid dosage > 50 MME, concurrent use of benzodiazepines, and medical comorbidities that increase the risk of overdose (eg, sleep apnea, pulmonary disease, heart failure).¹⁶ Prescribers should review prescription drug monitoring program data, when available, to assess treatment adherence and to obtain a collateral history that might suggest abuse or diversion. Urine drug testing can be a useful adjunct to ongoing therapy—again, to assess treatment adherence and look for evidence of other substance use disorders.

Watchfulness for misuse and OUD. Opioid misuse—the nontherapeutic use of opioids—includes taking opioids in amounts other than prescribed, for indications other than prescribed, and administering by alternative routes other than prescribed (eg, crushing and snorting, rather than ingesting). The presence of opioid misuse does not always signify OUD. However, The Diagnostic and Statistical Manual of Mental Disorders, 5th ed.,¹⁷ defines OUD as out-of-control use; devoting increasing mental and physical resources to obtaining, using, and recovering from substances; and continued use despite adverse consequences.

Behaviors that increase the risk of, and might signal, opioid misuse and OUD include¹⁸

• seeking early refills
• obtaining opioids from the emergency room
• using medications prescribed to others
• using opioids to treat symptoms other than pain, such as anxiety or insomnia
• “doctor-shopping.”

Continue to: Furthermore...

 

Furthermore, psychiatric comorbidities,¹⁹ a personal or family history of substance use disorder,²⁰ and a preadolescent history of sexual abuse²¹ are associated with a higher risk of a substance use disorder.

If OUD is identified, remain nonjudgmental and acknowledge that addiction is a chronic disease. Assumptions about a patient’s character or morality have no place in the appropriate management of OUD; remain mindful of your own implicit biases.

When is it appropriateto start an opioid taper?

The decision to taper opioids is difficult and can provoke anxiety for both prescriber and patient. Complicating matters is that there is insufficient evidence to evaluate opioid dosage-reduction interventions for patients with chronic noncancer pain.²²

Safety concerns. Even in patients who are taking opioids as prescribed and for whom no red flags have been raised, the long-term safety of high-dosage opioids remains unclear. There is no “safe” dosage of opioids; however, evidence is clear that the risk of death from overdose increases with dosage. Compared with patients taking a dosage anywhere from 1 to 20 MME/d, those taking 50 to 99 MME/d have a 3.7-fold increased risk of overdose; patients taking ≥ 100 MME/d had an 8.9-fold increased risk.²³ Patients for whom concomitant benzodiazepines are prescribed are also at higher risk of overdose and death. In studies of opioid overdose deaths, there was evidence of concurrent benzodiazepine use in 31% to 61% of cases.¹¹

Inadequate analgesia. Given the well-established risk of drug tolerance, the inability to achieve or maintain pain relief or functional improvement can still occur—even when the opioid dosage is escalated reasonably. It might be prudent in that situation to taper opioids while also considering alternative modalities, including ones that were deferred previously.

Continue to: Intolerable adverse effects

 

Intolerable adverse effects. Adverse effects are common. Constipation has a reported prevalence of 15% to 90% among patients on long-term opioid treatment.²⁴ Short-term, mild constipation is often manageable; long-term opioid use, however, can produce constipation refractory to bowel regimens and, in rare cases, lead to bowel obstruction, perforation, and even death. Other adverse effects include²⁵

• sedation and drowsiness
• impaired memory or concentration
• mood changes
• dry mouth
• abdominal pain and nausea
• sexual dysfunction.

When these effects limit the tolerability of treatment, tapering might be indicated.

How are opioids tapered?

There is no definitive evidence of an optimal rate of taper or frequency of follow-up. Most guidelines suggest tapering opioids at 10% of the dosage each week; patients who have been taking opioids for many years, however, might require a slower taper (eg, a dosage decrease of 5%-20% every 2-4 weeks).¹¹

Psychosocial support and maximizing nonopioid pain management techniques are critical to successful opioid tapering. When tapering is part of a comprehensive pain and rehabilitative plan, patients might find their symptoms alleviated.²⁶ Given the potential risks in patients taking both short- and long-acting opioids, tapering the long-acting opioid should be the initial priority.

Psychiatric comorbidities, a personal or family history of substance use disorder, and a preadolescent history of sexual abuse are associated with a higher risk of a substance use disorder.

A more rapid taper—eg, a 20% reduction each week or even abrupt discontinuation of opioids—might be necessary if diversion is suspected or if there is concern that continued use of the medication presents high risk. In such cases, consultation with an addiction medicine specialist can be helpful—to assess whether medication-assisted therapy for OUD would be appropriate and how to support patients who are having withdrawal symptoms.

Continue to: For all patients...

 

For all patients, frequent follow-up visits with their primary care clinician, as well as referrals to mental health, physical therapy, and pain or rehabilitation services, can promote a successful taper. It is advised that, before beginning a taper, a treatment plan should be written out with the patient so that expectations are shared by physician and patient for the goals of the taper, the speed of dosage decreases, and the frequency of follow-up after each dosage change. At each follow-up visit, education regarding self-management and individualized recommendations for psychosocial support, mental health services, and substance use disorder services should be updated.

Assessing risk when tapering chronic opioid therapy

The goals of tapering should be to (1) reduce adverse effects of treatment and (2) mitigate short- and long-term risks.

Three short-term risks

Unmasking OUD. Tapering prescribed opioids, or even just discussing tapering, can unmask OUD in some patients. Follow-up visits during the tapering schedule should include frequent screening for OUD. If OUD is diagnosed, we recommend beginning medication-assisted treatment or referring the patient to a substance use treatment center. There is strong evidence of the safety and efficacy of medication-assisted treatment, even with a coexisting chronic pain disorder.²⁷

Withdrawal syndrome. Opioid withdrawal syndrome is characterized by signs and symptoms of sympathetic stimulation, resulting from decreased sympathetic blockade by opioids (TABLE).²⁸ (See “Changes in the locus ceruleus lead to withdrawal.”²⁹) Symptoms start 2 to 3 half-lives after the last dose of opioid. Oxycodone, for example, has a half-life of 3 to 4 hours; withdrawal symptoms should therefore be anticipated in 6 to 12 hours. Because mixing opioids is commonplace, it can be difficult to predict exactly when withdrawal symptoms will begin. Patients are often most helpful in predicting the onset and severity of withdrawal symptoms.

Withdrawal can be measured using any of a number of validated tools, including

• the Subjective Opiate Withdrawal Scale, or SOWS³⁰ (FIGURE 1), which utilizes a patient self-report
• the Clinical Opiate Withdrawal Scale, or COWS³¹ (FIGURE 2), which relies on assessment made by the physician.

Continue to: Although withdrawal...

 

Although withdrawal is generally not considered life-threatening in patients without significant comorbidities, do not underestimate the severity of withdrawal symptoms. Often, the desire to avoid these intense symptoms drives patients with OUD to continue to overuse.

Increased pain. Patients might fear that pain will become worse if opioids are tapered. Although it is important to acknowledge this fear, studies of patients undergoing a long-term opioid taper report improvements in function without loss of adequate pain control; some even report that pain control improves.³²

Three long-term risks

Relapse. The most dangerous risk of tapering opioids is use of illicit opioids, a danger made worse by the increasing presence of highly lethal synthetic fentanyl analogues in the community. Risk factors for relapse following a full taper include the presence of depressive symptoms at initiation of tapering and higher pain scores at initiation and conclusion of the taper.³³ Having low pain at the end of an opioid taper, on the other hand, is predictive of long-term abstinence from opioids.³²

Declining function. As is the case while prescribing opioids for pain, maintenance of function remains a priority when tapering opioids. Function can be difficult to assess, given the many variables that can influence an individual’s function. Psychosocial factors, such as coping strategies and mood, strongly influence function; so do psychiatric morbidities, which are more prevalent in patients with chronic pain and disability, compared with the general population.³⁴

Medicolegal matters. Although difficult to characterize, medicolegal risk is an inevitable consideration when tapering opioids:

• In a study of closed malpractice claims involving all medical specialties, narcotic pain medications were the most common drug class involved, representing 1% of claims.³⁵
• In a study of closed malpractice claims involving pain medicine specialists, 3% were related to medication management. Most claims arose following death from opioid overdose.³⁶

Continue to: What else is needed in this area of practice?

 

 

What else is needed in this area of practice?

Increasingly, family physicians face the inherent tension of wanting to provide patient-centered, compassionate care for patients in pain while being mindful of opioid prescription stewardship. To support their work and help allay this tension, clinical research on this topic in the future should focus on

• new options for nonopioid pharmacotherapy for pain
• best practices for using opioids in noncancer chronic pain.

In addition, health care systems can help—by providing insurance coverage of nonpharmacotherapeutic options for treating pain.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 111 Westfall Road, Room 952, Rochester, NY 14620; MichaelMendoza@ monroecounty.gov

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

 

 

Dx seldom requires testing, but may take time to come into focus

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

 

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

 

 

Add-on therapy to treat the adverse effects of primary therapy

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

 

 

Consider tai chi, physical therapy to reduce falls

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; Michael_Mendoza@urmc.rochester.edu.

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

 

 

Dx seldom requires testing, but may take time to come into focus

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

 

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

 

 

Add-on therapy to treat the adverse effects of primary therapy

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

 

 

Consider tai chi, physical therapy to reduce falls

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; Michael_Mendoza@urmc.rochester.edu.

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

 

 

Dx seldom requires testing, but may take time to come into focus

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

 

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

 

 

Add-on therapy to treat the adverse effects of primary therapy

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

 

 

Consider tai chi, physical therapy to reduce falls

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; Michael_Mendoza@urmc.rochester.edu.