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9 Articles in Volume 6, Issue #2
Assessment and Treatment of Chronic Pain
Clinical Drug Testing for Pain Medicine
Epidural Indomethacin Alternative in Adult Onset Diabetics
Focus on Urine Drug Monitoring
Office-based Treatment of Opioid Physical Dependence
Oxycodone to Morphine Rotation
Pain Care at the End of Life
Tennant Blood Study—Summary Report
The Psychiatric Model of Treating Chronic Pain

Oxycodone to Morphine Rotation

The author describes one opioid rotational procedure found to be effective.

There is clear evidence that—with appropriate patient selection and opioid selection—outcomes, including improved function, are better when opioid therapy is considered in certain chronic non-terminal pain.1-3 With opioid therapy that may last a lifetime, opioid rotation will have to be periodically used to improve analgesia, minimize tolerance, and reduce side effects of opioid therapy in both malignant and non-malignant pain syndromes.3,4

Opioid rotation can be done by changing the drug or the route of administration.2,4 Long acting opioids have been associated with better analgesia, less side effects, better patient compliance and reduced risk of tolerance and aberrant drug behavior/addiction and abuse.4 Opioids, like methadone, have been a common rotation for one long acting opioid to another.4 However, in view of methadone’s association with drug addiction and its complex pharmacokinetics, many patients and doctors elect not to use it in chronic non-terminal pain conditions. This is further complicated by the fact that there may be incomplete cross-tolerance between opioids.3,4 This could be due to differences in opioid receptors, occupancy, or efficacy. Though opioid rotation has been associated with improved analgesia, there have been significant side effects during rotation.2,4 These include dose escalation, symptoms of overdose and, most annoyingly, withdrawal symptoms.2,4 The withdrawal symptoms vary in severity and include cold sweats, headaches, feeling cold, and insomnia.2,4 These symptoms can be quite distressing and can occur in up to 32% of cases of long acting opioid rotation.4

We attempted both rapid and gradual opioid rotation with the aim of finding a better rotation approach having less side effects and/or withdrawal symptoms.

Methodology

We attempted to covert a regimen of sustained release oxycodone (OSR) to sustained release morphine (MSR). Initially, we attempted to convert oxycodone to Morphine using a standard 1:1.5 ratio. This was done in single step over 7 to 10 days. This, however, resulted in poor compliance by the patient, mostly due to withdrawal symptoms. As a result, most patients abandoned the process.

To avoid these symptoms, we elected to do a gradual conversion from oxycodone SR to morphine SR. In this study, we converted only 50% of the initial oxycodone dose to long acting morphine, while the remaining 50% was left as sustained release oxycodone. For breakthrough pain, immediate release morphine (MSIR) was used. Every two weeks, a further 50% of the remaining dose of oxycodone was converted to morphine. Once the total daily dose of oxycodone was less than 30 mg, we discontinued all oxycodone and used only morphine along with MSIR, for breakthrough pain. Clonidine 0.1mg weekly patches were also used to reduce withdrawal symptoms.

Patient Selection

A total of 15 male patients (ages 34-52) taking 140-180mg of Oxycodone daily (in the form of both sustained release and immediate release for break through pain) for mechanical low back pain were included. Their pain syndromes did not respond to physical therapy nor interventional pain management. All of those selected had already failed the initial short period (7-10 days) conversion from oxycodone to morphine (1:1.5 ratio) due to withdrawal symptoms. All selected patients were free of any litigations (including worker compensation) to avoid potential symptoms magnification for secondary gain. Random urine testing confirmed the absence of illegal and/or non-prescribed opioid/drugs.

History and complete physical examination was performed. This included Waddell testing, McGill questionnaire, and pain drawings. All candidates signed opioid agreements and random urine testing was performed. None of the urine test came back positive for illicit drugs before the trial. Using the gradual tapering/ conversion (50% reduction from oxycodone to morphine sustained release), we were able to successfully convert all patients to morphine (both single dose and MSIR 15mg BID). The final ratio of morphine to oxycodone was 1:1-1.2. Three patients (20%) developed mild withdrawal symptoms. Pain relief was comparable to the analgesia provided by oxycodone derivatives. Two patients had mild itching (defined as not requiring any intervention). Three patients experienced nausea in the first week of the trial but, again, no treatment was needed.

Discussion

The use of opioid therapy in chronic non-malignant pain syndrome has been shown to improve the quality of life issues.1 There should be appropriate patient and opioid selection and co-morbid conditions such as depression and anxiety should be addressed to optimize the outcomes.1,9 The controversy of opioid use in chronic non-terminal pain comes from confusing addiction for tolerance that may result from chronic opioid therapy.1,2,4,9 While opioid therapy for both terminal and non-terminal pain syndrome is effective, side effects of opioid therapy have an important role in the success and/or failure of the treatment plan.1-4

Furthermore, treating physicians sometimes meet a required dose escalation due to tolerance with resistance. This is due to the fear of aberrant drug behavior including addiction or drug trafficking.1,3,5 Opioid rotation is a well-recognized method used to address rapid tolerance and other side effects of opioid therapy (sedation, altered mental status and aberrant drug behaviors).1,4,9

Opioid rotation is commonly used for malignant (terminal) pain syndromes.1,4 Opioid rotation can be accomplished by converting from short acting to long acting opioid, short acting to another short acting opioid, or long acting to another long acting opioid.4 Opioid rotation can also be done by altering the route of administration.2,4 Opioid rotation, while effective in treating tolerance and opioid side effects during therapy, can be associated with some difficulties. Part of the difficulty is due to the withdrawal symptoms that are associated with opioid rotation.4 This also includes dose escalation (over-dosage and sedation) or under-dosing (leading to increased pain).2,4 This may occur due to incomplete opioid cross tolerance, genetic polymorphism, difference in opioid receptor affinities, and/or different pharmacokinitics of the opioid or the delivery system.2,4,6

A good example of this phenomena is demonstrated in the use of codeine products. There is 7-10% of the population with lower CYP2D6 enzyme activity,6,8 which is needed to convert codeine to morphine and also is utilized in the metabolism of the R Isomer of methadone.6,7,8 This means that such patients would not have good analgesia with codeine and would instead express a preference for another opioid. This situation could be mistakenly interpreted as drug seeking behavior if the treating physician was unfamiliar with codeine metabolization deficiencies in some patients. This enzymatic difference is probably more prevalent in black Americans.6,8

On the other hand, these same patients may be overly sensitive to methadone due to slow metabolism of its R Isomer metabolites. A simple way to identify these patients is to test the urine for morphine metabolites following codeine therapy. If there are no morphine metabolites, then an abnormal enzyme should be suspected. Unfortunately, this test will not detect overly-fast CYP2D6 metabolizers in whom codeine is too rapidly metabolized and thus reduces the duration of analgesic effect.

Opioid rotation overdose can be another issue. This is because of incomplete cross tolerance or metabolic disorder (see above for methadone).2,4 Another cause is opioid receptor differences, e.g., methadone, which also has an NMDA antagonistic effect.1,2-4

Results

To avoid the genetic differences and gender effect in this study, we used the patient as their own control. We excluded any patient with litigations to avoid secondary gain effects or symptoms magnification. We also only selected patients with mechanical low back pain (nociceptive pain). We excluded patient with neuropathic pain as this can be more resistant to certain opioid therapies.4,9

This approach not only allowed us to do the opioid rotation in the case of oxycodone tolerance but, by testing urine during this process, the issue of negative test for oxycodone was resolved. This is due to the fact that most of the urine toxicology screening will show morphine and/or its metabolites. Whereas such negative urine tests may once have pointed to potential diversion of oxycodone,5,7 instead is now recognized as due to the normal metabolization of oxycodone.

Given the relationship between oxycodone and morphine, it is not clear why some patients(32%) had more severe withdrawal symptoms following total dose conversion from oxycodone to morphine when done in rapid step fashion.4 This could be to due to the difference in opioid receptors occupancy i.e. Mu vs. Kappa, or receptors occupancy/efficacy between morphine and oxycodone. This may be due to sensitivity of a specific opioid toward a particular receptor (or receptor subtype) that may vary between individuals. Another explanation could be the difference in intrinsic efficacy among opioids. This relationship between receptor occupancy and drug effect may vary even for drugs that act on the same receptors. This could explain the difference of effect on two different opioids acting on same receptor (e.g. mu or Kappa, etc.)9

Another possible contributory factor may be differences in the pharmacokinetics or drug delivery between sustained release oxycodone and sustained release morphine. The differences may impact the oral bioavailibilty of the opioid.9

For all the above reasons, opioid rotation for chronic non-terminal pain should be done more frequently. Indeed Do Quang-Cantagrel et al found that the first opioid prescribed was effective in only 36% of patients; there were side effects in 30%; and it was ineffective in 34% of the cases. A second opioid was prescribed when the first opioid failed in 31%, a third opioid in 40%, and a fourth in 56%, and finally a fifth rotation in 14% of cases before successful analgesia was achieved.9

Also of interest, is that the final total dose of morphine (combined sustained release and MSIR) in this rotation procedure was even less than the expected dose suggested by the 1:1.5-2 ratio conversion ratio from oxycodone to morphine as recommended by most authors.2,4

We found that the described approach to opioid rotation, while lengthy, was easier to adapt and patient compliance was better than the alternative rapid conversion from oxycontin to morphine. There were no dropouts during the process.

Only three patients had mild to moderately-severe withdrawal symptoms (20%). This is better than the 32% incidence of withdrawal symptoms reported by Thompsen et al in their conversion from one long acting opioid to another long acting opioid.4 Furthermore, there was no incidence of patient sedation in our study. Other side effects (nausea, drowsiness,and itching) were mild and no treatment was required.

A review of publications, in which at least three to four opioid rotations were performed during opioid treatment of chronic pain,4,9 indicates a 32% inci-dence of withdrawal symptoms. Another drawback of rapid opioid rotation was dose escalation, which we did not observe in these patients. We believe that a slow conversion process can reduce these side effects4,9 and, in so doing, end up with a final dose less than anticipated from published conversion ratios.

Conclusion

Rotation between long-acting opioids is often a clinical necessity. For often unexplained reasons, one opioid may lose its effectiveness due to tolerance or other metabolic change. However, gradual tapering/conversion will reduce the side effects of opioid withdrawals and avoid dose escalation.

We used sustained release morphine given in a single dose and that made compliance easier. Another benefit is that morphine can be easily detected in most urine toxicology screens. However, this same gradual reduction/conversion can be used for other opioid rotations.

While the sample size of fifteen patients in this study was rather small (due to the difficulty of finding patients having the same gender, a similar pain syndrome (nociceptive), and taking the same drug), we feel that our findings are valid and look forward to findings in other rotation studies.

Last updated on: December 20, 2011
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