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Opiate Rotation, Incomplete Cross-Tolerance, and Hyperalgesic Metabolites

Alexander DeLuca, M.D.; Addiction, Pain, and Public Health website -; 2001-08-06; Modified: 2005-12-25


 [Related resources =]
[Related resources =]
See also:
Opioid Rotation in Patients with Cancer Pain - Bruera et al.; Cancer; 78(4); 852-857; 1996
Psychostimulants as Adjuvant Analgesics Bruera and Watanabe; J Pain Symptom Manage.; 1994

This is very cutting edge stuff, and I feel that I don't understand it completely or explain it as clearly as it could be by someone wiser and more experienced than myself, but here is my best effort, as of 8/6/01. Be sure and look over the references at the bottom of this page, and the "See also:" links, above.

The major discovery is that the classic opioids like morphine, oxycodone, fentanyl, and Dilaudid (hydromorphone) break down into metabolites that are 'hyperalgesic', that is, molecules that can actually cause pain when they accumulate under conditions of chronic administration.

This might explain the experience of switching to more and more potent opioids which in turn produce more and more hyperalgesic molecules, and so a vicious cycle develops.

Methadone is different. It breaks down to methadone which is not a hyperalgesic substance.

The next part is non-intuitive: the higher the dose of the chronically taken opioid, the more relatively potent the methadone is when you rotate to it.

If you were to calculate the equianalgesic dose of methadone using the usual conversion tables, you will massively overdose the patient. Therefore, in an opioid rotation to methadone you calculate the equianalgesic dose and divide by three, usually, or at least by two.

So in the rotation, you are losing a lot of opioid tonnage. You also have to be very careful during the first week on methadone as it accumulates in the body. So if a person is rotated to methadone at an appropriate dose and is experiencing pain on day two, the correct thing to do would be to observed the patient for a few more days before raising the dose of methadone, and as the drug accumulates he will perhaps become pain free. If, after an appropriate rotation procedure, the person is showing signs of sedation, fatigue and grogginess, the dose of methadone might have to be decreased over the first week.

It's more simple than it sounds. In the case of a man with intractable headaches for 31 years(!) who had been referred to me by his headache specialist for detoxification to rule out opiate rebound as the etiology of headache, I did, after a long time, manage to get him from fentanyl 75 patch to the fentanyl 50 patch and using less breakthrough dilaudid, but his pain was still 8-9 every day.

This was unacceptable. After phone consultation with three pain specialists, and review of several articles they recommended, I discontinued the fentanyl and rotated the patient to methadone at a little more than 1/3 of the dose indicated by equianalgesic conversion tables.

After rotation he ended up on 10 mg methadone 5 times per day with headache pain down to 3-4 (!!!) and only occasional need for breakthrough meds. I tried to 'go for the gold' and raised his methadone to 15mg 5 times per day, the headache pain was essentially eliminated, but at the expense of severe fatigue and nodding. Adding Adderall (amphetamine) to the regimen at 40mg daily in 3 divided doses gave relief from the fatigue which allowed the patient to tolerate the higher and more effective methadone dose. 

Amphetamine also has analgesic properties of it's own and is synergistic with opioid analgesia (1+1=3) so this is a rational regimen. (see References below.) This patient ended up requiring zero breakthrough medication beyond "a couple of Excedrin, but not every day."

In two other patients, who were doing well on high dose MS-Contin and Oxy-Contin, I did the rotation to methadone because it is so much less expensive. They are also doing fine on methadone, although one now requires the fentanyl lollipop (Actiq - oral transmucosal fentanyl) as a breakthrough medication. The other patient is on lower doses of methadone and is using dilaudid as a breakthrough medication successfully.


The first three references are from the syllabus of the American Society of Addiction Medicine (ASAM) conference Pain and Addiction: Common Threads II, in Los Angeles, 4/2001. Course Co-Directors: Howard Heit, M.D., FACP, FASAM and Seddon Savage, M.D., FASAM.  This syllabus is probably available from ASAM. The main ASAM office phone number is: 301-656-3920.

1)  "Incomplete cross tolerance and multiple mu opioid peptide receptors"

Gavril W. Pasternak published in Trends in Pharmacological Sciences, Vol. 22, No 2, Feb 2001

This article presents the underlying theoretical of incomplete cross tolerance on which the practice of opioid rotation to methadone is based. This is dense and difficult to understand material; I keep rereading it and I still can't complete get it.

But, the next reference is the nuts and bolts of opiate rotation:

2) "Dose Ratio between Morphine and Methadone in Patients with Cancer Pain"

Lawlor, Turner, Hanson, and Bruera in Cancer 1998;82;1167-73

Conclusion: "The results highlight the general underestimation of methadone potency and the consequent risk of potential life-threatening toxicity. The strongly positive correlation between dose ratio and previous morphine dose suggests the need for a highly individualized and cautious approach when rotating from morphine to methadone in patients with cancer pain."

For more on this same subject:

3) "Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: Comparison of two clinical experiences."

Ripamonti, DeCono, Groff, Belzile, Pereira, Hanson, and Bruera in Annals of Oncology 9;79-83;1998

"Results: The results of this retrospective study suggest that:

1) methadone is much more potent than previously described in the literature, and

2) the dose ratio between hydromorphone (dilaudid) and methadone is higher than as suggested by equianalgesic tables, and

3) the ratio correlates with total opioid dose administered before switching."

Conclusions: "The fact that methadone ratio is different according to the opioid dose used previously should be taken into careful consideration by the clinician in order to avoid severe toxicity or death during switchover. Prospective studies should be carried out in order to better define our findings."

4) "Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance"

Bespalov AY, Zvartau EE, Beardsley PM;
Neurosci Biobehav Rev 2001 Jun ;25(4):343-353

ABSTRACT - Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly

5) "Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine"

Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W; Pain 2001 Aug ;93(2):155-163

ABSTRACT - We have previously shown that methadone maintenance patients are hyperalgesic. Very little is known about the antinociceptive effects of additional opioids in these patients. This study (1) compared the intensity and duration of antinociceptive responses, at two pseudo- steady-state plasma morphine concentrations (C(SS1) and C(SS2)), between four patients on stable, once daily, doses of methadone and four matched control subjects; and (2) determined, in methadone patients, whether the antinociceptive effects of morphine are affected by changes in plasma R(-)-methadone concentration that occur during an inter-dosing interval. Two types of nociceptive stimuli were used: (1) a cold pressor test (CP), (2) electrical stimulation (ES). Morphine was administered intravenously to achieve the two consecutive plasma concentrations. Blood samples were collected, concurrently with nociceptive responses, to determine plasma morphine concentrations. Methadone patients achieved mean C(SS1) and C(SS2) of 16 and 55 ng/ml respectively; those of controls were 11 and 33 ng/ml. Methadone patients were hyperalgesic to pain induced by CP but not ES. Despite significantly greater plasma morphine concentrations, methadone patients experienced minimal antinociception in comparison with controls. Furthermore in methadone patients, the antinociception ceased when the infusion ended. In comparison, the duration of effect in control subjects was 3 h. The fluctuations that occurred in plasma R(-)- methadone concentration during an inter-dosing interval had little effect on patients' responses to morphine. Our findings suggest that methadone patients are cross-tolerant to the antinociceptive effects of morphine, and conventional doses of morphine are likely to be ineffective in managing episodes of acute pain amongst this patient group. Further research is needed to determine whether other drugs are more effective than morphine in managing acute pain in this patient population

6) "Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent"

Compton P, Charuvastra VC, Ling W; Drug Alcohol Depend 2001 Jul 1 ;63(2):139-146

ABSTRACT - Patients on methadone maintenance therapy are relatively intolerant of pain, a finding hypothesized to reflect a hyperalgesic state induced by chronic opioid administration. To explore if the intrinsic activity of the opioid maintenance agent might affect expression of hyperalgesia in this population, withdrawal latency for cold-pressor (CP) pain was compared between small groups of methadone-maintained (n = 18), buprenorphine-maintained (n = 18), and matched control (n = 18) subjects. The opioid-maintained groups had equal and significantly shorter withdrawal latencies than controls, however it is possible that high rates of continued illicit opioid use precluded finding differences between methadone and buprenorphine groups. Differential effects of maintenance agent were found for the few subjects without illicit opioid use, such that withdrawal latencies for methadone- maintained (n = 5) were less than for buprenorphine-maintained (n = 7) which were less than controls (n = 18). Diminished pain tolerance in patients receiving opioid maintenance treatment has significant clinical implications. More research is needed to determine if buprenorphine offers advantages over methadone in this regard

7) "Amphetamine and Analgesia" - British National Formulary 35 (March 1998) p186

8) "Psychostimulants as Adjuvant Analgesics"

Eduardo Bruera and Sharon Watanabe; Journal of Pain and Symptom Management; 9(6); 412-415; 1994.



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Alexander DeLuca, M.D.

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Originally posted: 2005-12-25

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