Ketamine Relieves Pain at End of Life

DENVER – The variety of administration routes and dosing protocols for ketamine make it useful for analgesia in the palliative care setting.

Ketamine seems effective in a variety of difficult pain syndromes commonly encountered in hospice and palliative medicine, Dr. Eric Prommer observed at the conference. Multiple routes of administration make ketamine a valuable weapon in the setting of refractory pain.

The most common and best-studied routes of administration are the intravenous, oral, and subcutaneous approaches. Uncommon routes come in handy when others become problematic and include sublingual, intranasal, and topical administration.

"Ketamine is both water and lipid soluble. That’s the beauty of ketamine: It’s what allows multiple routes of administration and generally reliable absorption," explained Dr. Prommer, director of palliative care at the Mayo Clinic Hospital in Scottsdale, Ariz.

Ketamine is on the World Health Organization’s essential drug list for refractory cancer pain, but there is no agreement on the best protocol, dose, or method of administration for optimal analgesia. Perhaps that element of uncertainty drew the packed house for Dr. Prommer’s plenary lecture, in which he filled in the blanks in a ketamine analgesia literature dominated by uncontrolled studies leavened by a limited number of randomized trials and growing anecdotal experience.

At present, ketamine’s best role is as an adjuvant analgesic prescribed in order to avoid escalation of opioid dosing.

"There is really only limited data looking at giving ketamine instead of opioids. That needs to be studied further," he stressed.

Ketamine’s main method of action involves binding to the NMDA receptor. This receptor mirrors the opioid receptor such that everywhere in the CNS that there’s an opioid receptor, there is also an NMDA receptor. As an NMDA antagonist, ketamine reverses opioid tolerance. So when a patient on both ketamine and opioids develops sedation as a prominent adverse effect, look to reduce the opioid dose. It’s unlikely that ketamine prescribed in the subanesthetic doses used for pain relief is the culprit.

Unlike methadone, ketamine has no major drug interactions that could affect its bioavailability.

Adverse effects occur in dose-dependent fashion in up to 20%-30% of patients on intravenous ketamine at 200-350 mg/day. The chief side effects are psychomimetic and involve altered visuospatial perceptions, or a "spaced out" feeling. Delirium, dizziness, altered hearing, tachycardia, hypertension, and nausea and vomiting can also occur. Adverse effects are less frequent with oral dosing. Prophylactic administration of haloperidol at 0.5 mg or lorazepam at 0.5 mg for the first few doses of ketamine lessens the risk of side effects.

Urinary toxicity is a recently recognized side effect of ketamine. Manifestations include interstitial cystitis, hydronephrosis, vesicoureteric reflux, and renal impairment, including irreversible renal failure. Mostly, however, urinary toxicity occurs in long-term "street" ketamine abusers.

"We don’t see a lot of this in our population because they’re typically not on ketamine for a prolonged time," he noted.

The starting intravenous bolus dose of ketamine is typically 0.25-0.50 mg/kg given over 30 minutes. Onset of effect is within 60 seconds, with a duration of 3-4 hours.

Oral ketamine is simply the intravenous solution mixed in a flavored syrup to mask the unpleasant taste; spearmint and cherry flavorings are popular. Oral dosing is 0.5 mg/kg. Onset is in about 20 minutes. The dose can be repeated three or four times per 24 hours. A recent study showed that a 1:1 dose ratio for conversion from subcutaneous to oral dosing is safe and effectively maintains analgesia in patients with cancer pain (J. Pain Symptom Manage. 2011;41:1098-105).

Sublingual ketamine at 25 mg works well for breakthrough pain. "That number – 25 mg – comes up a lot in the literature. If you extrapolate that to a 70-kg person that’s a nice subanesthetic dose," according to Dr. Prommer.

The intranasal route is another really important backup option for breakthrough pain. The dose is 50 mg.

Topical 1%-2% ketamine cream compounded in a pharmacy and applied three times daily to affected areas is effective for neuropathic pain. Another topical option in neuropathic pain syndromes – and one supported by an open-label study – is topical 2% amitriptyline/1% ketamine, which was well tolerated and associated with moderate to complete patient satisfaction over 6-12 months (J. Pain 2005;6:644-9).

"The beauty of the topical route is there is minimal systemic absorption, so you don’t have to worry about any kind of significant adverse effects. There seems to be a dose-response relationship. I’ve given up to 10% ketamine topically and patients have tolerated it," Dr. Prommer said.

A particularly exciting method of giving ketamine for refractory pain is the so-called "burst technique." It entails a 3- to 5-day continuous subcutaneous infusion with dose escalation. Upon stopping the ketamine, pain relief lasting 2 weeks or longer is common.

"Once you silence that NMDA receptor you might get prolonged effects. This is really wonderful for our palliative care/hospice population because it means they get one less medication while it adds to their comfort. You can’t get better than that: a medicine that you can stop and still get some mileage out of it," he continued.

In the Australian multicenter VCOG PM 1-00 study, the burst ketamine protocol used in palliative care patients with refractory cancer pain began with a continuous subcutaneous infusion of 100 mg/24 hours. If that proved ineffective after 24 hours, the dose was increased to 300 mg/24 hours. And if patients didn’t have good analgesia after 24 hours on ketamine at 300 mg/24 hours, the dose was bumped to 500 mg/24 hours. When the effective or maximum tolerated dose was reached, it was continued for 3 days and then stopped. Thus, patients ceased taking ketamine after a maximum of 5 days whether it was effective or not.

Half of patients were rated as responders using strict criteria and 9% became pain free. Moreover, 50% of responders experienced pain relief lasting 2 weeks or longer while off ketamine. The toxicities were mainly neurologic and occurred at 300 or 500 mg/24 hours dosing (J. Palliat. Care 2010;26:176-83).

"It was very interesting: There really weren’t a lot of cardiovascular adverse effects in this study," Dr. Prommer commented.

A variant of the burst technique proved effective in patients with complex regional pain syndrome type 1 in a Dutch placebo-controlled study. The 60 participants had a median 7.4-year disease duration. Investigators utilized a 4.2-day intravenous infusion of low-dose ketamine with individualized stepwise tailoring of dosage based upon pain relief and side effects. The final dose was 22.2 mg/hour/70 kg. Pain relief in the ketamine group lasted for nearly 12 weeks after the drug was stopped (Pain 2009;145:304-11).

Other randomized studies show efficacy for ketamine in patients with post-herpetic neuralgia or ischemic pain. But Dr. Prommer stressed that while it’s clear ketamine provides relief in patients with chronic noncancer pain, he believes the drug’s long-term use should be restricted to the clinical trial setting.

"There are just no good long-term safety data for 6-8 months of therapy," he emphasized.

Dr. Prommer said a single dose of ketamine is helpful for painful dressing changes when adequate analgesia can’t be gained with opioids alone. Case reports attest to the usefulness of ketamine as an oral rinse in patients with mucositis; however, Dr. Prommer has tried it and found it didn’t work.

He reported having no financial conflicts.

DENVER – The variety of administration routes and dosing protocols for ketamine make it useful for analgesia in the palliative care setting.

Ketamine seems effective in a variety of difficult pain syndromes commonly encountered in hospice and palliative medicine, Dr. Eric Prommer observed at the conference. Multiple routes of administration make ketamine a valuable weapon in the setting of refractory pain.

The most common and best-studied routes of administration are the intravenous, oral, and subcutaneous approaches. Uncommon routes come in handy when others become problematic and include sublingual, intranasal, and topical administration.

"Ketamine is both water and lipid soluble. That’s the beauty of ketamine: It’s what allows multiple routes of administration and generally reliable absorption," explained Dr. Prommer, director of palliative care at the Mayo Clinic Hospital in Scottsdale, Ariz.

Ketamine is on the World Health Organization’s essential drug list for refractory cancer pain, but there is no agreement on the best protocol, dose, or method of administration for optimal analgesia. Perhaps that element of uncertainty drew the packed house for Dr. Prommer’s plenary lecture, in which he filled in the blanks in a ketamine analgesia literature dominated by uncontrolled studies leavened by a limited number of randomized trials and growing anecdotal experience.

At present, ketamine’s best role is as an adjuvant analgesic prescribed in order to avoid escalation of opioid dosing.

"There is really only limited data looking at giving ketamine instead of opioids. That needs to be studied further," he stressed.

Ketamine’s main method of action involves binding to the NMDA receptor. This receptor mirrors the opioid receptor such that everywhere in the CNS that there’s an opioid receptor, there is also an NMDA receptor. As an NMDA antagonist, ketamine reverses opioid tolerance. So when a patient on both ketamine and opioids develops sedation as a prominent adverse effect, look to reduce the opioid dose. It’s unlikely that ketamine prescribed in the subanesthetic doses used for pain relief is the culprit.

Unlike methadone, ketamine has no major drug interactions that could affect its bioavailability.

Adverse effects occur in dose-dependent fashion in up to 20%-30% of patients on intravenous ketamine at 200-350 mg/day. The chief side effects are psychomimetic and involve altered visuospatial perceptions, or a "spaced out" feeling. Delirium, dizziness, altered hearing, tachycardia, hypertension, and nausea and vomiting can also occur. Adverse effects are less frequent with oral dosing. Prophylactic administration of haloperidol at 0.5 mg or lorazepam at 0.5 mg for the first few doses of ketamine lessens the risk of side effects.

Urinary toxicity is a recently recognized side effect of ketamine. Manifestations include interstitial cystitis, hydronephrosis, vesicoureteric reflux, and renal impairment, including irreversible renal failure. Mostly, however, urinary toxicity occurs in long-term "street" ketamine abusers.

"We don’t see a lot of this in our population because they’re typically not on ketamine for a prolonged time," he noted.

The starting intravenous bolus dose of ketamine is typically 0.25-0.50 mg/kg given over 30 minutes. Onset of effect is within 60 seconds, with a duration of 3-4 hours.

Oral ketamine is simply the intravenous solution mixed in a flavored syrup to mask the unpleasant taste; spearmint and cherry flavorings are popular. Oral dosing is 0.5 mg/kg. Onset is in about 20 minutes. The dose can be repeated three or four times per 24 hours. A recent study showed that a 1:1 dose ratio for conversion from subcutaneous to oral dosing is safe and effectively maintains analgesia in patients with cancer pain (J. Pain Symptom Manage. 2011;41:1098-105).

Sublingual ketamine at 25 mg works well for breakthrough pain. "That number – 25 mg – comes up a lot in the literature. If you extrapolate that to a 70-kg person that’s a nice subanesthetic dose," according to Dr. Prommer.

The intranasal route is another really important backup option for breakthrough pain. The dose is 50 mg.

Topical 1%-2% ketamine cream compounded in a pharmacy and applied three times daily to affected areas is effective for neuropathic pain. Another topical option in neuropathic pain syndromes – and one supported by an open-label study – is topical 2% amitriptyline/1% ketamine, which was well tolerated and associated with moderate to complete patient satisfaction over 6-12 months (J. Pain 2005;6:644-9).

"The beauty of the topical route is there is minimal systemic absorption, so you don’t have to worry about any kind of significant adverse effects. There seems to be a dose-response relationship. I’ve given up to 10% ketamine topically and patients have tolerated it," Dr. Prommer said.

A particularly exciting method of giving ketamine for refractory pain is the so-called "burst technique." It entails a 3- to 5-day continuous subcutaneous infusion with dose escalation. Upon stopping the ketamine, pain relief lasting 2 weeks or longer is common.

"Once you silence that NMDA receptor you might get prolonged effects. This is really wonderful for our palliative care/hospice population because it means they get one less medication while it adds to their comfort. You can’t get better than that: a medicine that you can stop and still get some mileage out of it," he continued.

In the Australian multicenter VCOG PM 1-00 study, the burst ketamine protocol used in palliative care patients with refractory cancer pain began with a continuous subcutaneous infusion of 100 mg/24 hours. If that proved ineffective after 24 hours, the dose was increased to 300 mg/24 hours. And if patients didn’t have good analgesia after 24 hours on ketamine at 300 mg/24 hours, the dose was bumped to 500 mg/24 hours. When the effective or maximum tolerated dose was reached, it was continued for 3 days and then stopped. Thus, patients ceased taking ketamine after a maximum of 5 days whether it was effective or not.

Half of patients were rated as responders using strict criteria and 9% became pain free. Moreover, 50% of responders experienced pain relief lasting 2 weeks or longer while off ketamine. The toxicities were mainly neurologic and occurred at 300 or 500 mg/24 hours dosing (J. Palliat. Care 2010;26:176-83).

"It was very interesting: There really weren’t a lot of cardiovascular adverse effects in this study," Dr. Prommer commented.

A variant of the burst technique proved effective in patients with complex regional pain syndrome type 1 in a Dutch placebo-controlled study. The 60 participants had a median 7.4-year disease duration. Investigators utilized a 4.2-day intravenous infusion of low-dose ketamine with individualized stepwise tailoring of dosage based upon pain relief and side effects. The final dose was 22.2 mg/hour/70 kg. Pain relief in the ketamine group lasted for nearly 12 weeks after the drug was stopped (Pain 2009;145:304-11).

Other randomized studies show efficacy for ketamine in patients with post-herpetic neuralgia or ischemic pain. But Dr. Prommer stressed that while it’s clear ketamine provides relief in patients with chronic noncancer pain, he believes the drug’s long-term use should be restricted to the clinical trial setting.

"There are just no good long-term safety data for 6-8 months of therapy," he emphasized.

Dr. Prommer said a single dose of ketamine is helpful for painful dressing changes when adequate analgesia can’t be gained with opioids alone. Case reports attest to the usefulness of ketamine as an oral rinse in patients with mucositis; however, Dr. Prommer has tried it and found it didn’t work.

He reported having no financial conflicts.

DENVER – The variety of administration routes and dosing protocols for ketamine make it useful for analgesia in the palliative care setting.

Ketamine seems effective in a variety of difficult pain syndromes commonly encountered in hospice and palliative medicine, Dr. Eric Prommer observed at the conference. Multiple routes of administration make ketamine a valuable weapon in the setting of refractory pain.

The most common and best-studied routes of administration are the intravenous, oral, and subcutaneous approaches. Uncommon routes come in handy when others become problematic and include sublingual, intranasal, and topical administration.

"Ketamine is both water and lipid soluble. That’s the beauty of ketamine: It’s what allows multiple routes of administration and generally reliable absorption," explained Dr. Prommer, director of palliative care at the Mayo Clinic Hospital in Scottsdale, Ariz.

Ketamine is on the World Health Organization’s essential drug list for refractory cancer pain, but there is no agreement on the best protocol, dose, or method of administration for optimal analgesia. Perhaps that element of uncertainty drew the packed house for Dr. Prommer’s plenary lecture, in which he filled in the blanks in a ketamine analgesia literature dominated by uncontrolled studies leavened by a limited number of randomized trials and growing anecdotal experience.

At present, ketamine’s best role is as an adjuvant analgesic prescribed in order to avoid escalation of opioid dosing.

"There is really only limited data looking at giving ketamine instead of opioids. That needs to be studied further," he stressed.

Ketamine’s main method of action involves binding to the NMDA receptor. This receptor mirrors the opioid receptor such that everywhere in the CNS that there’s an opioid receptor, there is also an NMDA receptor. As an NMDA antagonist, ketamine reverses opioid tolerance. So when a patient on both ketamine and opioids develops sedation as a prominent adverse effect, look to reduce the opioid dose. It’s unlikely that ketamine prescribed in the subanesthetic doses used for pain relief is the culprit.

Unlike methadone, ketamine has no major drug interactions that could affect its bioavailability.

Adverse effects occur in dose-dependent fashion in up to 20%-30% of patients on intravenous ketamine at 200-350 mg/day. The chief side effects are psychomimetic and involve altered visuospatial perceptions, or a "spaced out" feeling. Delirium, dizziness, altered hearing, tachycardia, hypertension, and nausea and vomiting can also occur. Adverse effects are less frequent with oral dosing. Prophylactic administration of haloperidol at 0.5 mg or lorazepam at 0.5 mg for the first few doses of ketamine lessens the risk of side effects.

Urinary toxicity is a recently recognized side effect of ketamine. Manifestations include interstitial cystitis, hydronephrosis, vesicoureteric reflux, and renal impairment, including irreversible renal failure. Mostly, however, urinary toxicity occurs in long-term "street" ketamine abusers.

"We don’t see a lot of this in our population because they’re typically not on ketamine for a prolonged time," he noted.

The starting intravenous bolus dose of ketamine is typically 0.25-0.50 mg/kg given over 30 minutes. Onset of effect is within 60 seconds, with a duration of 3-4 hours.

Oral ketamine is simply the intravenous solution mixed in a flavored syrup to mask the unpleasant taste; spearmint and cherry flavorings are popular. Oral dosing is 0.5 mg/kg. Onset is in about 20 minutes. The dose can be repeated three or four times per 24 hours. A recent study showed that a 1:1 dose ratio for conversion from subcutaneous to oral dosing is safe and effectively maintains analgesia in patients with cancer pain (J. Pain Symptom Manage. 2011;41:1098-105).

Sublingual ketamine at 25 mg works well for breakthrough pain. "That number – 25 mg – comes up a lot in the literature. If you extrapolate that to a 70-kg person that’s a nice subanesthetic dose," according to Dr. Prommer.

The intranasal route is another really important backup option for breakthrough pain. The dose is 50 mg.

Topical 1%-2% ketamine cream compounded in a pharmacy and applied three times daily to affected areas is effective for neuropathic pain. Another topical option in neuropathic pain syndromes – and one supported by an open-label study – is topical 2% amitriptyline/1% ketamine, which was well tolerated and associated with moderate to complete patient satisfaction over 6-12 months (J. Pain 2005;6:644-9).

"The beauty of the topical route is there is minimal systemic absorption, so you don’t have to worry about any kind of significant adverse effects. There seems to be a dose-response relationship. I’ve given up to 10% ketamine topically and patients have tolerated it," Dr. Prommer said.

A particularly exciting method of giving ketamine for refractory pain is the so-called "burst technique." It entails a 3- to 5-day continuous subcutaneous infusion with dose escalation. Upon stopping the ketamine, pain relief lasting 2 weeks or longer is common.

"Once you silence that NMDA receptor you might get prolonged effects. This is really wonderful for our palliative care/hospice population because it means they get one less medication while it adds to their comfort. You can’t get better than that: a medicine that you can stop and still get some mileage out of it," he continued.

In the Australian multicenter VCOG PM 1-00 study, the burst ketamine protocol used in palliative care patients with refractory cancer pain began with a continuous subcutaneous infusion of 100 mg/24 hours. If that proved ineffective after 24 hours, the dose was increased to 300 mg/24 hours. And if patients didn’t have good analgesia after 24 hours on ketamine at 300 mg/24 hours, the dose was bumped to 500 mg/24 hours. When the effective or maximum tolerated dose was reached, it was continued for 3 days and then stopped. Thus, patients ceased taking ketamine after a maximum of 5 days whether it was effective or not.

Half of patients were rated as responders using strict criteria and 9% became pain free. Moreover, 50% of responders experienced pain relief lasting 2 weeks or longer while off ketamine. The toxicities were mainly neurologic and occurred at 300 or 500 mg/24 hours dosing (J. Palliat. Care 2010;26:176-83).

"It was very interesting: There really weren’t a lot of cardiovascular adverse effects in this study," Dr. Prommer commented.

A variant of the burst technique proved effective in patients with complex regional pain syndrome type 1 in a Dutch placebo-controlled study. The 60 participants had a median 7.4-year disease duration. Investigators utilized a 4.2-day intravenous infusion of low-dose ketamine with individualized stepwise tailoring of dosage based upon pain relief and side effects. The final dose was 22.2 mg/hour/70 kg. Pain relief in the ketamine group lasted for nearly 12 weeks after the drug was stopped (Pain 2009;145:304-11).

Other randomized studies show efficacy for ketamine in patients with post-herpetic neuralgia or ischemic pain. But Dr. Prommer stressed that while it’s clear ketamine provides relief in patients with chronic noncancer pain, he believes the drug’s long-term use should be restricted to the clinical trial setting.

"There are just no good long-term safety data for 6-8 months of therapy," he emphasized.

Dr. Prommer said a single dose of ketamine is helpful for painful dressing changes when adequate analgesia can’t be gained with opioids alone. Case reports attest to the usefulness of ketamine as an oral rinse in patients with mucositis; however, Dr. Prommer has tried it and found it didn’t work.

He reported having no financial conflicts.