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Long-acting opioids can help alleviate the pain associated with severe, refractory chronic daily headaches.
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Medication options for patients with severe, refractory, chronic daily headache (CDH) remain limited. The choices include opioids;1,2 amphetamines; monoamine oxidase inhibitors(MAOIs),3 with or without tricyclic antidepressants, beta-blockers, or calcium blockers; daily triptans; or dihydroergotamine (DHE).4 The use of daily opioids for nonmalignant pain, such as CDH, remains somewhat controversial.5,6 Previous studies have demonstrated that in a small number of refractory headache patients, opioids can result in a greatly enhanced quality of life.1,2

While the short-acting opioids often lead to rebound headaches and overuse, this is not observed as often with the longer-acting ones. This study compares three different long-acting opioids in severe, chronic, daily headache patients: sustained-release (SR) morphine sulfate; methadone; and controlled-release (CR) oxycodone.


The patients in this study, ages 22 to 62, were all long-term patients at the Robbins Headache Clinic. Each patient had the diagnosis of chronic daily headache, refractory to the usual medication regimens. The patients were interviewed after six months of opioid therapy. Efficacy, side effects, and quality of life were assessed.

Sustained-Release (SR) Morphine Sulfate Patients

Sixty-seven patients, ages 22 to 62, were placed on SR morphine (Kadian). Thirty-one of those patients discontinued the morphine prior to six months due to lack of efficacy and/or side effects.

Dose of SR Morphine: Sustained-release morphine was dosed initially at 20 mg per day, and usually increased after four days to 20 mg every 12 hours. Twenty-six of the 36 patients who remained on the drug continued on 20 mg every 12 hours. Seven patients remained on only 20 mg, once daily, and three were increased to 50 mg once daily. These are relatively low doses of morphine. If higher doses seemed necessary, sustained-release morphine was discontinued, and different medication options were explored.

Pharmacokinetics of SR Morphine: The morphine sulfate utilized in this study was an oral formulation of sustained-released pellets contained in a gelatin capsule. For cancer pain, this formulation often is dosed once per day. The pharmacokinetics are linear, and approximately 20 to 40 percent of the oral dose reaches the systemic circulation.7,8 This form of morphine achieves steady state in two days, and maintains adequate blood levels for up to 24 hours after a single dose. Many patients in the current study found that dosing twice daily was more effective than once per day. The time to Tmax is long (8.6 hours) after one dose. The Cmin is higher, with a similar Cmax, compared to other available forms of long-acting morphine.7

With this formulation, “end-of-dose withdrawal” is rarely seen.


Sixty-six patients, 53 women and 13 men ages 26 to 58, were placed on methadone. Thirty-two patients discontinued the methadone prior to six months due to lack of efficacy and/or side effects.

Dose of Methadone: The doses were started at 2.5 mg (one-half of a 5 mg tablet), and were increased slowly, as tolerated, to 5 mg twice daily. If needed, the dose was pushed to a limit of 30 mg per day. The average dose was 10 mg per day, a relatively small amount of methadone. Two patients were maintained on only 2.5 mg per day.

Pharmacokinetics of Methadone: The long, but unpredictable, half-life of methadone (average half-life of 24 hours) is both an asset and a liability.9 Rebound headaches are usually not observed, but typically an accumulation of medication produces cognitive side effects. The dose must be carefully titrated. Methadone produces an analgesic effect that persists for five to eight hours; however, this can be longer.10 After four to seven days of fixed-interval dosing, sustained analgesia can be maintained. A smaller dose may then be required to avoid drug accumulation. Oral meth-adone is stronger than oral morphine, and 20 to 30 mg of methadone is equal to 60 to 90 mg of morphine.11 Oral methadone has a bioavailability of 85 percent, with an oral to parenteral potency ratio of 1:2.

Efficacy of Long-Acting Opioids in Severe Chronic Daily Headaches
Relief Morphine (n=67) Methadone (n=66) Oxycodone (n=52)
0 to 25% (no relief) 36% (24/67) 41% (27/66) 46% (24/52)
25 to 50% (mild) 13% (9/67) 8% (5/66) 17% (9/52)
50 to 75% (moderate) 21% (14/67) 24% (16/66) 21% (11/52)
75 to 100% (excellent) 30% (20/67) 27% (18/66) 15% (8/52)
Combined excellent
and moderate relief 51% (34/67) 51% (34/66) 36% (19/52)

Controlled-Release (CR) Oxycodone

Fifty-two patients, ages 24 to 57, were placed on CR oxycodone (Oxycontin). Thirty-three patients stopped the CR oxycodone prior to six months, due to lack of efficacy and/or side effects.

Dose of CR Oxycodone: Oxycontin was dosed initially at 10 mg once or twice daily. If needed, the dose was pushed to a limit of 20 mg three times a day (60 mg per day maximum). The average daily dose was 32 mg.

Pharmacokinetics of CR Oxycodone: The bioavailability of CR oxycodone is equal to immediate-release (IR) oxycodone, but the time to Tmax is delayed (1.5 hours for IR oxycodone, and three hours for CR oxycodone).12 Time to onset of relief with CR oxycodone is approximately one hour compared to 40 minutes for the oxycodone IR.13 Duration of relief is eight to 12 hours for CR oxycodone, compared to six to seven hours for IR oxycodone.13 Most patients remedicate at 12 hours with CR oxycodone, compared to eight to nine hours with the IR form.

With CR oxycodone, there is a biphasic absorption pattern: initial release, followed by prolonged, steady release. Levels of CR oxycodone remain steady over 12 hours following CR oxycodone administration.12,14 Trough levels are approximately 50 percent of peak. Plasma levels are steady with CR oxycodone, as compared to the unpredictability of methadone. Doubling the dose from 10 mg to 20 mg doubles the peak and trough concentrations.14,15

Last updated on: May 16, 2011
First published on: May 1, 2001