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6 Articles in Volume 1, Issue #3
Breaking Down the Barriers of Pain: Part 3
CES: A Practical Protocol for theTreatment of Pain
New Directions
Pharmaceutical Therapies
The Neural Plasticity Model of Fibromyalgia Theory, Assessment, and Treatment: Part 1


Long-acting opioids can help alleviate the pain associated with severe, refractory chronic daily headaches.

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

Controlled-release oxycodone is available in 10 mg, 20 mg, and 40 mg tablets. CR oxycodone 10 mg every 12 hours is just as effective as 5 mg of the IR form every six hours.13 Most patients with chronic nonmalignant pain need 20 mg to 40 mg daily. Oxycodone is demethylated to noroxycodone and oxymorphone.13 While the analgesic effect of noroxycodone is negligible, the oxymorphone is active. However, it is the oxycodone itself that is the primary drug responsible for analgesia.15


The efficacy of long-acting opioids in severe chronic daily headache patients was assessed. Table 1 outlines the results of the study.

Side Effects

Each drug has its share of side effects. Tables 2, 3, and 4 show the side effects and incidence of such.

Quality of Life

The SR morphine patients were not assessed for quality of life, but patients in the study who took methadone and CR Oxycodone were. Tables 5 and 6 outline the results.

SR Morphine Sulfate Side Effects
Side Effect Number %
Constipation 21 30
Somnolence 18 26
Nausea or vomiting 17 25
Increased headache 6 9
Dry mouth 5 7
Anxiety or hyperactive 5 7
Blurred vision 5 7
Itching/rash 4 6
Insomnia 4 6
Dizzy/lightheaded 3 4
Depression 2 3
DIfficulty concentrating 2 3
Anorexia 1 1.5
Muscle Pain 1 1.5
Methadone Side Effects
Side Effect Number %
Fatigue 13 20
Dizzy/lightheaded 13 20
Constipation 12 18
Confusion 9 14
Nausea/GI upset 9 14
Profuse sweating 6 9
Rash (allergic) 2 3
CR Oxycodone Side Effects
Side Effect Number %
Constipation 17 33
Somnolence 15 29
Nausea 14 27
Vomiting 6 12
Increased headache 5 10
Dry mouth 4 8
Dizzy/lightheaded 4 8
Itching 3 6
Anxiety or nervousness 3 6
Euphoria 3 6
Blurred vision 2 4
DIfficulty concentrating 2 4
Insomnia 2 4
Anorexia 1 2
Methadone – Quality of Work and Home Life
The patients who continued on the methadone were asked the following questions pertaining to quality of life:
Yes No
Has work performance, or work as a homemaker, improved significantly? 88% 12%
Has your relationship with your spouse significantly improved? 74% 26%
Have your relationships with your children or friends significantly improved? 82% 18%
Have you had an improvement in sexual activity or in your sexual life? 53% 47%
CR Oxycodone – Quality of Work and Home Life
The patients who continued on the CR oxycodone were asked the following questions pertaining to quality of life:
Yes No
Has work performance, or work as a homemaker, improved significantly? 84% 16%
Has your relationship with your spouse significantly improved? 79% 21%
Have your relationships with your children or friends significantly improved? 68% 32%

Addiction and Previous Prescription Opiate Overuse

Addictive behavior toward the drug was observed in six percent of the SR morphine patients, in three percent of those on methadone, and in 13 percent 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, 22 of the 67 (33 percent) had previously overused short-acting opioids; 14 of these 22 (64 percent) had moderate or excellent relief at six months. These 14 did not display addictive behaviors toward the SR morphine.

In the methadone group, 16 patients out of 66 (24 percent) had previously overused short-acting prescription opiates. Only one of these 16 overused the methadone. Seven of these 16 patients (44 percent) did well on long-term methadone, with moderate or excellent relief. Previous opiate abuse was not examined in the CR oxycodone group.


Tolerance developed in 19 of the 34 patients (56 percent) 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 seen in 12 of the 34 patients (35 percent) 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 12 of the 19 patients (63 percent) who continued on CR oxycodone for six months.


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 Opioids in Patients with Anxiety or Depression

In the SR morphine group, 29 of the 67 patients (43 percent) were diagnosed with anxiety. Thirteen of the 29 (45 percent) patients with anxiety did well long-term with the morphine.

Thirty-six out of the 67 patients (54 percent) in the SR morphine group were previously diagnosed with depression. Eighteen of 36 patients (50 percent) 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.


The patients in this study had a long history of severe chronic daily headaches 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. Higher drop-out rates were encountered over longer periods of time. However, many patients stopped the opioids for several months, and experienced enhanced efficacy after restarting. Others switched to a different long-acting opioid when the current one was no longer effective.

After six months of therapy, a higher percentage of patients continued with SR morphine or methadone than with CR oxycodone. The SR morphine and meth-adone provided moderate or excellent relief in a higher percentage of patients than 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. 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 and would allow more patients to remain on the medication. Fatigue is also often a problem among CDH patients, and this may be exacerbated by the opioids. At times, we counter this with stimulant medication. Although this adds to potential addiction, the stimulants may be helpful for the headache as well as the fatigue. The nausea associated with opioids is difficult to combat. We generally do not want to add additional medication to treat adverse effects.

While tolerance to the opioids was observed frequently, every effort was made not to accelerate the dose. Low doses were utilized in these patients, with daily doses averaging 40 mg daily for SR morphine, 10 mg for methadone, and 32 mg for CR oxycodone. 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 was 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 indicators 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 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 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 does not accurately predict abuse of the long-acting medications.1 A number of patients who 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 and necessitates more careful monitoring, when prescribing the long-acting ones. Overuse of opioids is more likely to occur in patients with the following diagnoses: borderline or narcissistic personality disorders (and to a lesser degree, other personality disorders); severe anxiety disorder; previous opioid, drug, or alcohol abuse (particularly recent);18 and unstable or abusive family situations.19

Opioids may ease depression in certain patients via 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, depressed patients, when assessed after six months, did just as well as non-depressed patients. Depression in opiate withdrawal is more likely with meth-adone than with the others.1 Bipolar disorder 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 disorder were more likely to overuse opioids, particularly when they were not adequately treated with mood stabilizers.1 However, a number of the bipolar patients have done well with long-acting opioids.1

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 another previous study (submitted for publication) involving SR morphine for severe CDH, 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 CR oxycodone.1 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-dose” phenomenon, with “mini-withdrawals” (downslope withdrawals) throughout the day; 2) less obsession with waiting for the next dose, dosing twice daily instead of prn dosing; 3) more stable blood levels; 4) acetaminophen and aspirin, in combination narcotics, are not present in these longer acting preparations; and 5) 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 controlled.24 Suicide is a greater risk in this population.25,26 Despite these factors, chronic non-malignant pain and chronic daily headache remain undertreated. Reasons for this include: fear of side effects and fear of addiction among patients and physicians; physicians’ fear (justified) of the wrath of medical boards, the DEA, and the courts;27 the health care system places pain relatively low on its scale of priorities; and insufficient knowledge about the treatment of chronic non-malignant pain.28,29

For a limited number of severe, refractory 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. n

Signals of 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 medication;16
  3. Much of the office visit time is spent on 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 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,” or “I need twice as much at one time because of insurance”;
  6. Concurrent use of other addictive or illicit drugs;
  7. Selling the drug;
  8. The patient has been obtaining similar medication from other physicians;
  9. There is an acceleration of the dose without proper discussion with the physician.17
Last updated on: May 16, 2011
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