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Sustained-Release Morphine Sulfate For
Severe Chronic Daily Headache
Lawrence Robbins, MD
Posted February 2000

Approximately 50% of patients with chronic daily headache (CDH) respond adequately to preventive medications. For those with severe, refractory chronic daily headache, the medication options are limited. The use of opioids for nonmalignant pain is controversial. Previous studies with methadone or controlled-release oxycodone have been promising in CDH pts. The patients in this study had all failed the standard medications.

67 patients, ages 22 to 62, had the diagnosis of refractory CDH, and were interviewed after six months of therapy. 31 of the patients stopped sustained-release morphine sulfate (Kadian) prior to 6 months. The average dose was 20 mg twice daily. 26 of the 36 patients who remained on sustained-release morphine continued on 20 mg twice daily. 7 remained on only 20 mg daily, and 3 were increased to 50 mg daily. 24(36%) had no relief, 9(13%) had mild relief, 14(21%) had moderate relief, and 20(30%) reported excellent relief.

29 patients had a history of anxiety. 11(38%) of these reported no relief of the headaches, 5(17%) stated mild relief, 6(21%) had moderate relief, and 7(24%) reported excellent relief.

36 pts. had a history of depression. 10/36(28%) reported no relief of the headaches, 8(22%) had mild relief, 6(17%) had moderate relief, and 12(33%) reported excellent relief.

Side effects included: constipation (30%), somnolence (26%), nausea or vomiting (25%), increased headache (9%), dry mouth (7%), anxiety (7%), blurred vision (7%), itching/rash (6%), insomnia (6%), dizziness (4%), depression (3%), and difficulty concentrating (3%).

Tolerance developed in 19 of the 34 patients who continued on the drug. Every effort was made not to increase the dose. Addictive behavior was observed in 4 patients. 22 of the 67 patients had previously overused or abused prescription medications, and only 2 of these patients abused the morphine. 14 of the 22 pts. who previously overused prescription medications had moderate or excellent relief from the morphine sulfate.

Descriptors. morphine, chronic daily headache, headache, opioids, Kadian

Only approximately 50% of patients with chronic daily headache (CDH) respond adequately to preventive medications1. For those remaining with severe, refractory, chronic daily headaches, the medication options are limited. These choices include monoamine oxidase inhibitors (MAOI’s), amphetamines, opioids, daily triptans or daily dihydroergotamine, and botulinum toxin2. Each of these approaches has major limitations, and this group of patients is exceedingly difficult to treat.

The use of opioids for nonmalignant pain is controversial3,4,5. Previous studies, primarily with methadone6,7 or controlled–release oxycodone8,9, have shown that a limited number of patients do respond well, with a definitely enhanced quality of life. In the current study, the patients had failed standard medications (NSAIDs/calcium channel blockers/beta blockers/sodium valproate/antidepressants – including MAOI’s/methysergide/triptans/etc.) and non-medication strategies (psychotherapy, exercise, massage, pain management strategies, acupuncture, exercise, biofeedback – relaxation, etc.).

In the current retrospective study, a unique long-acting form of sustained-release morphine sulfate, Kadian, was assessed for efficacy and tolerability.

The 67 patients, ages 22 to 62, were all long-term patients at the Robbins Headache Clinic. Each patient had the diagnosis of refractory chronic daily headache. The patients were interviewed after six months of sustained-release morphine therapy. Efficacy and side effects were assessed. Thirty-one of the patients stopped the medication prior to completing six months of treatment due to ineffective results, or intolerable side effects.

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 circulation10,11. 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 daily. 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 morphine10. With this formulation, "end-of-dose withdrawal" is rarely seen.

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 morphine was discontinued, and different medication options were explored.

Table 1
Efficacy of Sustained-Release Morphine for Severe CDH
Number of patients = 67 (assessed after 6 months);
31 patients stopped the morphine prior to 6 months.

Relief of CDH Number of
Pts. = 67
% Of Total Pts.
0 – 25%
(No Relief)
24 36%
(Mild Relief)
9 13%
(Moderate Relief)
14 21%
(Excellent Relief)
20 30%
34 51%

Table 2
Efficacy in Patients with Anxiety
29/67 (43%) diagnosed with anxiety
Relief of CDH Number of
Pts. = 29
% Of Anxious Pts.
0 – 25%
(No Relief)
11 38%
(Mild Relief)
5 17%
(Moderate Relief)
6 21%
(Excellent Relief)
7 24%
13 45%

Table 3
Efficacy in Patients with Depression>
36/67 (54%) diagnosed with depression
Relief of CDH Number of
Pts. = 36
% Of Depressed Pts.
0 – 25%
(No Relief)
10 28%
(Mild Relief)
8 22%
(Moderate Relief)
6 17%
(Excellent Relief)
12 33%
18 50%

Table 4
Side Effects (67 total patients)
Side Effect Number of
Patients = 67
% of Patients
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%

Tolerance, Addiction, and Previous Prescription Drug Abuse
Tolerance developed in nineteen of the thirty-four patients (56%) who continued on the drug for six months. Every effort was made not to increase the daily dose. Sustained-release morphine sulfate was discontinued if patients required more than 50 mg per day.

Addictive behavior was observed in four patients, requiring drug discontinuation. Twenty-two of the sixty-seven patients (33%) previously had overused or abused prescription opiates; yet only two of these patients abused the morphine. Fourteen of the twenty-two patients (64%), who previously had abused or overused prescription opiates, had moderate or excellent relief at six months. These fourteen patients did not display addictive behaviors towards the sustained-release morphine.

In the current study, 51% of severe, refractive CDH patients achieved moderate or excellent relief after six months of therapy. The other 49% of patients were withdrawn off of morphine because of side effects and/or lack of efficacy. This group of patients also had failed multiple previous medication regimens.

We previously examined similar groups of CDH patients who had been placed on methadone or controlled-release oxycodone6,8. Similar results were seen in the methadone group, with 51% of 66 patients having moderate or excellent relief after six months. The average dose of methadone was 10 mg per day. In the controlled-release oxycodone group, 36% of the fifty-two patients achieved moderate or excellent relief. The average dose of oxycodone was 32 mg per day.

A significant percentage of patients reported side effects from sustained-release morphine, with the top three adverse effects being constipation, somnolence, and nausea. Side effects were similar with methadone, but lightheadedness was seen more often with the methadone6. Upon discontinuation, withdrawal was more severe with methadone than with controlled-release oxycodone, and was the least with the sustained-release morphine. This was due presumably to the very long-acting nature of this form of morphine. The side-effect profile for sustained-release morphine was similar to that of controlled-release oxycodone.

Among those patients with comorbid anxiety, moderate or excellent relief from the headache was seen in 45%. While narcotics are anxiolytic for many people, they should not be utilized for this purpose. In previous studies, methadone was found to be more likely to decrease anxiety than was oxycodone9. In these studies, while many of the patients stated that opioids did decrease their anxiety, this did not necessarily translate into fewer headaches. Patients with anxiety occasionally overused the opioids because of the anxiolytic effect. Many of the patients using methadone or oxycodone did describe the response triad of rush/tranquil/tired", characteristic of narcotics9. Because of the very long-acting nature of this formulation of sustained-release morphine, most patients have not felt euphoria from this drug. While anxious patients may benefit secondarily from the narcotics, the anxiolytic effect of the narcotic can lead, at times, to overuse.

In the current study, 50% of patients with comorbid depression had moderate or excellent relief of headaches from the sustained-release morphine. In previous studies with narcotics, patients similarly have noted that headaches were improved, and, as a secondary result, depression was eased9. Methadone was more likely than oxycodone to increase depression, particularly during withdrawal. While several bipolar patients in previous studies did well, patients with a diagnosis of bipolar disorder were more likely, in general, to overuse the opioids9.

Tolerance was seen in 56% of the patients in the current study who continued on the drug for at least six months. The dose was not usually increased. This author feels that it is crucial, in the long-term treatment of chronic daily headache patients, not to escalate doses. At times, switching narcotics for one to two months, and then returning to the original narcotic, allows patients to utilize smaller doses for a longer period of time12,13.

Previous studies have revealed that patients with certain personality disorders are more likely to overuse the medications. In addition, those with severe anxiety, previous drug or alcohol abuse, or unstable or abusive family situations were found to be at increased risk14,15. A positive response to short-acting opioids (codeine, hydrocodone, etc.) was previously found to indicate that patients might do well on the longer-acting opioids9. With this formulation of sustained-release morphine, we found a lower rate of overuse among those patients, who previously overused other drugs, than was seen with methadone or oxycodone.

In assessing addiction, there is a need for improved identification of "prescription opioid abuse" in the chronic daily headache population16. The following are criteria that may be helpful in signaling opioid abuse: 1. The patient demonstrates an obsessive concern about having the drug; 2. There are many calls and disturbances at the office about the medication; 3. There are questionable or recurrent stories about why the patient needs an early refill; 4. The patient has been found to be hoarding the drug; 5. The patient is concurrently utilizing street drugs and/or alcohol; 6. The patient has been obtaining similar medication from other physicians; and 7. There is an acceleration of the dose without adequate discussion with the physician16. Any of these, by itself, does not qualify as prescription opioid abuse, but rather it is the overall picture that needs to be considered.

In prescribing daily opioids, meticulous monitoring and record-keeping of medication effects, prescription patterns, and patient responses are essential. While contracts and informed consent are important, there is doubt as to whether they truly inhibit overuse. Frequent monitoring and demonstration of efficacy are important in the long-term prescription of these opioids17.

While success rates in previous studies with long-acting opioids are relatively low, these patients have few options, and have failed previous treatment modalities6,8,9. Without treatment, they are left chronically ill, and often chronically disabled. The long-acting opioids have the following advantages: maintenance of stable blood levels; avoidance of unnecessary acetaminophen and aspirin; decreased risk of overuse; and avoidance of "end-of-dose" phenomenon, with "mini-withdrawals" throughout the day. The opioids should not be used as a sole modality, but rather as part of an integrated "biopsychosocial" approach. As adjunctive therapy, exercise, psychotherapy, physical therapy, relaxation or yoga, and biofeedback may be employed.

The sustained-release morphine sulfate formulation used in this study has been helpful in the long-term treatment of severe, refractory chronic-daily-headache patients. For a small number of these patients, the long-acting opioids may provide an otherwise unobtainable improvement in quality of life7.

Acknowledgements: The author wishes to thank Charles Ludmer, MD, and Halleh Akbarnia, MD, for their editorial assistance.


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