Shannon Langner, MD

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.² An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).² Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).² However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.⁵

[polldaddy:9724288]

STUDY SUMMARY

Melatonin tops amitriptyline in >50% improvement in headache frequency

This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.¹ Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.

The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).

WHAT’S NEW

An effective migraine prevention alternative with minimal adverse effects

Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.