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Long-Acting Opioids For Severe, Refractive Chronic
Daily Headache: Sustained-Release
Morphine, Methadone, and Controlled-Release Oxycodone
Lawrence Robbins, MD and Halleh Akbarnia, MD
Posted March 2000
 

Abstract
Three forms of long-acting opioids were utilized for severe, refractive chronic daily headache. Patients were interviewed after six months of opioid therapy. 67 patients had been given sustained-release (SR) morphine sulfate, 66 patients were placed on methadone, and 52 had been treated with controlled-release (CR) oxycodone. By six months, 46% of the patients had discontinued the morphine, 48% the methadone, and 63% the CR oxycodone. Low doses were utilized, with the average dose of SR morphine being 40 mg daily, methadone 10 mg, and CR oxycodone 32 mg.

After six months, 51% of the SR morphine patients, as well as 51% of those on methadone, reported moderate or excellent relief. 36% of those on CR oxycodone had moderate or excellent relief at six months. Constipation, somnolence, and nausea were commonly reported by those on SR morphine, as well as those on CR oxycodone. Fatigue, dizziness, and constipation were the most frequently encountered side effects with methadone.

Quality of work and home life was assessed in those who continued on the methadone and CR oxycodone. Work performance and relationships greatly improved in the patients who remained on the opioids.

Addictive behavior towards the drug was observed in 6% of the SR morphine patients, in 3% of those on methadone, and in 13% of the CR oxycodone patients. Previous prescription opiate abuse did not translate into overuse of the long-acting opioids. 33% of those on SR morphine had previously overused prescription opioids, and the majority of these (64%) had moderate or excellent relief at six months, without overuse of the medication. Only one of the sixteen patients who had previously overused opioids abused the methadone. Seven of these sixteen (44%), did well long-term on the methadone.

Tolerance was observed in 56% of patients of those who continued on SR morphine, in 35% of those on methadone, and in 63% of the CR oxycodone patients. Every effort was made not to accelerate doses. Withdrawal symptoms were more severe with methadone than the other opioids.

Long-acting opioids are beneficial for a limited number of severe, refractive chronic daily headache patients.

Key Words: opioids, chronic daily headache, sustained-release morphine, methadone, controlled-release oxycodone

Introduction
The medication options for patients with severe, refractive chronic daily headache (CDH) remain limited. The choices include: opioids^1,2; amphetamines; monoamine oxidase inhibitors³ (MAOIs) (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 readily 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.

Methods
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, refractive to the usual medication regimens. The patients were interviewed after six months of therapy on the opioid. Efficacy, side effects, and quality of life were assessed.

Sustained – Release (SR) Morphine Sulfate Patients
Sixty-seven patients, ages 22 to 62, had been 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, usually increasing after four days to 20 mg every twelve hours. Twenty-six of the thirty-six patients who remained on the drug continued on 20 mg every twelve 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 orphine 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% 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 twenty-four hours after a single dose. Many patients in the current study found that twice daily dosing was more effective than once per day. The time to T_max is long (8.6 hours) after one dose. The C_min is higher, with a similar C_max, compared to other available forms of long-acting morphine⁷. With this formulation, "end-of-dose withdrawal" is rarely seen.

Methadone
Sixty-six patients, fifty-three women and thirteen men ages 26 to 58, had been 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 5 mg, half-tablet daily, and this was 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 twenty-four hours) is both an asset and a liability⁹. Rebound headaches are typically 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 5 to 8 hours; however, this can be longer¹⁰. After four to seven days of fixed interval dosing, sustained analgesia may be maintained. A smaller dose may then be required to avoid drug accumulation. Oral methadone is stronger than oral morphine, and 20 to 30 mg of methadone is equal to 60 to 90 mg of morphine¹¹. Oral methadone has a bioavailability of 85 percent, with an oral to parenteral potency ratio of 1:2.

Controlled-Release (CR) Oxycodone
52 patients, ages 24 to 57, had been placed on CR oxycodone (Oxycontin). Thirty-three patients stopped the CR oxycodone prior to six months.

Dose of CR Oxycodone:
Oxycontin was initially dosed 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 T_max is delayed (1.5 hours for IR oxycodone, 3 hours for CR oxycodone)¹². Time to onset with CR oxycodone is approximately one hour compared to forty minutes for the oxycodone IR¹³. Duration of relief is eight to twelve hours for CR oxycodone, compared to six to seven hours for IR oxycodone¹³. Most patients remedicate at twelve hours with CR oxycodone, compared to the eight to nine hours with the immediate release form.

With CR oxycodone, there is a biphasic absorption pattern: initial release, followed by prolonged, steady release. Levels of CR oxycodone remain steady over twelve hours following CR oxycodone administration^12,14. Trough levels are approximately 50% 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.

Controlled-release oxycodone is available in 10 mg, 20 mg and 40 mg tablets. 10 mg of CR oxycodone every twelve hours is just as effective as 5 mg of the IR form every six hours¹³. Most patients with chronic nonmalignant pain need 20 mg to 40 mg daily. Oxycodone is demethylated to noroxycodone and oxymorphone¹³. While the noroxycodone is negligible, the oxymorphone is active. However, it is the oxycodone itself that is the primary drug responsible for the analgesic effect¹⁵.

Results:

Quality of Life
The SR morphine patients were not assessed for quality of life.

Addiction and Previous Prescription Opiate Overuse
Addictive behavior towards the drug was observed in 6% of the SR morphine patients, in 3% of those on methadone, and in 13% of the CR oxycodone patients.

Previous prescription opiate abuse did not necessarily translate into overuse or abuse of the long-acting opioids. Among the SR morphine patients, twenty-two of the sixty-seven (33%) had previously overused short-acting opioids; fourteen of these twenty-two (64%) had moderate or excellent relief at six months. These fourteen did not display addictive behaviors towards the SR morphine.

In the methadone group, sixteen patients out of sixty-six (24%) had previously overused short-acting prescription opiates. Only one of these sixteen overused the methadone. Seven of these sixteen patients (44%) did well long-term on the methadone, with moderate or excellent relief. Previous opiate abuse was not examined in the CR oxycodone group.

Tolerance
Tolerance developed in nineteen of the thirty-four patients (56%) who continued on sustained-release morphine sulfate for six months. Every effort was made not to increase the daily dose. SR morphine was discontinued if patients required more than 50 mg daily.

Tolerance was also seen in twelve of the thirty-four patients (35%) who continued on methadone for at least six months. While the dose was increased to 30 mg per day in several patients, if larger doses were required, the methadone was discontinued.

Tolerance also developed in twelve of the nineteen patients (63%) who continued on CR oxycodone for six months.

Withdrawal
Among the three opioids, methadone produced the most severe and prolonged withdrawal symptoms. Several patients had prolonged withdrawal symptoms, up to six weeks, even after discontinuing the methadone.

Efficacy of the Opioids in Patients with Anxiety or Depression
In the SR morphine group, twenty-nine of the sixty-seven patients (43%) were diagnosed with anxiety. Thirteen of the twenty-nine (45%) patients with anxiety did well long-term with the morphine.

Thirty-six out of the sixty-seven patients (54%) in the SR morphine group were previously diagnosed with depression. Eighteen of thirty-six patients (50%) did well long-term, with moderate or excellent relief after six months.

Anxiety and depression were not formally studied in the methadone or CR oxycodone groups.

Discussion
The patients in this study had a long history of severe chronic daily headache poorly responsive to the usual preventive medications. Because of the enhanced quality of life, they were willing to tolerate the side effects, the inconvenience of obtaining the opioids, and associated stigma. In the current study, efficacy was assessed over six months; we do encounter higher dropout rates over longer periods of time. However, many patients stop the opioids for several months, with enhanced efficacy after restarting, or they switch to a different long-acting opioid when the current one is no longer effective.

After six months of therapy, a higher percentage of patients continued with SR morphine or methadone than CR oxycodone. The SR morphine and methadone provided moderate or excellent relief in a higher percentage of patients than was observed with CR oxycodone. Among those who did continue on the medication, quality of life was greatly enhanced.

Side effects are a major reason for discontinuation of the opioids. The constipation may be very severe. While many of the adverse effects, such as constipation, may lessen over time, this is not always the case. Research has begun on a new medication that reverses opioid-induced constipation; this would allow more patients to remain on the medication. Fatigue is often a problem among CDH patients, and this may be exacerbated by the opioids. At times we counter this with stimulant medication, but this adds to potential addiction. The stimulants may be helpful for the headache as well as the fatigue. The nausea associated with the opioids is difficult to combat; we generally do not want to add additional medication to treat adverse effects.

While tolerance to the opioids was frequently observed, every effort was made not to accelerate the dose. Low doses were utilized in these patients, with SR morphine averaging 40 mg daily, methadone 10 mg, and CR oxycodone 32 mg. For the long-term treatment of CDH, it is important to maintain the patient on relatively low doses of opioids. In our experience, those patients who require large doses of daily opioids rarely are able to continue on them for extended periods of time.

Addiction to the long-acting opioids is relatively uncommon. In assessing prescription opioid addiction, DSM IV and WHO criteria are inadequate. We need separate criteria for the determination of ‘prescription opioid abuse’¹⁶. The following may be helpful in signaling opioid abuse: 1. The patient demonstrates an overwhelming concern or obsession for the drug; 2. There are multiple calls and disturbances at the office about the medication¹⁶; 3. Much of the office visit time is spent on concern and discussion about the drug; 4. The patient continuously calls early for refills; 5. The patient calls with stories such as "the medicine fell down the sink" "I left it in a hotel room" "My dog ate it" "It spilled on the floor" "My friend hurt himself and was desperate and I gave him some" "My friend is an addict and stole it" "The pharmacy only gave me half" "I need twice as much at one time because of insurance"; 6. Concurrent use of alcohol, marijuana, cocaine, etc; 7. Selling the drug. 8. The patient has been obtaining similar medication from other physicians; and 9. There is an acceleration of the dose without adequate discussion with the physician¹⁷.

The above problems should serve as a warning to the physician that the patient may be abusing the medicine. It is the degree, frequency, and pervasiveness with which the above criteria occur that determines whether the opioid should be discontinued. Unfortunately, since these are "end of the line" patients, there are few alternative choices available. However, when abuse does occur, it is dangerous for the patient and the physician to continue prescribing opioids.

A positive response to short-acting opioids is often a good indication that the patient will do well with the longer-acting medications. Previous opioid overuse did not always accurately predict abuse of the long-acting medications¹. A number of patients who had previously overused short-acting opioids have done well for years on the longer-acting ones. However, in general, previous overuse of the short-acting opioids is a concern when prescribing the long-acting ones. Patients more likely to overuse the opioids include: borderline or narcissistic personality disorders (and to a lesser degree, other personality disorders); those with severe anxiety; previous opioid, drug, or alcohol abuse (particularly recent)¹⁸; and unstable or abusive family situations¹⁹.

The opioids may ease depression in certain patients via either a direct effect or by decreasing the headache pain. A few patients become depressed as an adverse effect of the medication itself. In a previous study (submitted for publication) involving SR morphine for severe CDH, the depressed patients, when assessed after six months, did just as well as the non-depressed patients. Opiate withdrawal may precipitate depression; this is more likely with the methadone than the others¹. Bipolar illness is seen more frequently in the migraine population^20,21. Substance abuse is common among those who are bipolar. As a group, patients with a diagnosis of bipolar were more likely to overuse the opioids, particularly when they were not adequately treated with mood stabilizers¹. However, a number of the bipolar patients have done well long-term with the opioids¹.

The opioids are anxiolytic for many patients. However, this effect did not necessarily translate into fewer headaches. Patients occasionally overused the medication due to the anxiety. In one previous study (submitted for publication) involving SR morphine for severe CDH, the anxious patients responded to the opioid at the same rate as those without anxiety. In previous studies, methadone was more likely to decrease anxiety than was CR oxycodone¹. While anxious patients may benefit from the anxiolytic effects of opioids, this can lead to overuse. In these patients, if the opioids did not significantly decrease the headache, they were discontinued.

While long-term success rates may be relatively low with the opioids, these patients have few options. The advantages of long-acting opioids in treating chronic pain are several: 1. avoidance of the "end-of-the-dose" phenomenon with "mini-withdrawals" throughout the day; 2. with consistent dosing twice daily, there is less of the medication obsession seen with PRN dosing; 3. blood levels are more stable; 4. the acetaminophen and aspirin seen in combination narcotics is not present in these long-term preparations; and 5. there is a decreased risk of addiction^22,23.

The health and psychological consequences of untreated chronic pain are staggering; quality of life suffers greatly when the pain is not controlled²⁴. Suicide is always a risk in this population^25,26. Despite this, chronic non-malignant pain and chronic daily headache remain undertreated. Reasons for this include: 1. fear of side effects and addiction among patients and physicians; 2. physicians’ fear (justified) of the wrath of medical boards, the DEA, and the courts²⁷; 3. the health care system places pain relatively low on its scale of priorities, and 4. insufficient knowledge about the treatment of chronic nonmalignant pain^28,29.

For a limited number of severe, refractive CDH patients, long-acting opioids may be effective and enhance quality of life. With proper patient selection, and close monitoring, the opioids deserve a role in the treatment of chronic daily headache.

Acknowledgements: The authors wish to thank Charles Ludmer, MD for his editorial assistance.

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