Alexander DeLuca, M.D.
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Opioid rotation, incomplete tolerance, and hyperalgesia in patients on chronic opioid therapy

Search terms: "opioid, hyperalgesic, tolerance, chronic pain, methadone"

Search date: 10/26/2001 - References added 10/29/01

See also: "Opiate rotation, incomplete cross-tolerance, and hyperalgesic metabolites"

Reference 1:

Gavril W. Pasternak "Incomplete cross tolerance and multiple mu opioid peptide receptors" 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.

Reference 2:

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

"Dose Ratio between Morphine and Methadone in Patients with Cancer Pain" by 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."

Reference 3:

For more on this same subject:

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


Reference 4:

Bespalov AY, Zvartau EE, Beardsley PM Department of
Psychopharmacology, Valdman Institute of Pharmacology, Pavlov Medical
University, 6/8 Lev Tolstoy Str., St Petersburg 197089, Russia.

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

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

Reference 5:

Doverty M, White JM, Somogyi AA, Bochner F, Ali R,  Ling W

Department of Clinical and Experimental Pharmacology,
University of Adelaide, SA 5005, Adelaide, Australia. 

  Pain 2001 Feb 1 ;90(1-2):91-96

" Hyperalgesic responses in methadone maintenance patients"

ABSTRACT - Opioid substitution treatment for dependence may alter
sensitivity to pain. Previous studies on pain sensitivity in
methadone maintenance patients have yielded contradictory results.
This study compared nociceptive responses between 16 patients on
stable, once daily, doses of methadone and 16 matched control
subjects. Two types of nociceptive stimuli were used: (1) electrical
stimulation; and (2) a cold pressor test. Two parameters were
measured: detection for onset of pain, and pain tolerance. Methadone
patients were tested over an inter-dosing period: at the time of
trough plasma methadone concentration (0 h), and 3 h after their
daily dose. Control subjects were tested twice 3 h apart. Blood
samples were collected to determine plasma methadone concentration.
In methadone patients, trough to peak increases in mean R-(-)- and
S-(+)-methadone concentrations (118 and 138 ng/ml to 185 and 259
ng/ml, respectively) resulted in significant increases in pain
detection and tolerance values for both nociceptive stimuli. Using
electrical stimulation, methadone patients' pain tolerance values
were lower than controls at 0 h, but higher than controls at 3 h; no
significant differences in pain detection values were found. For the
cold pressor test, methadone patients detected pain significantly
earlier than controls at 0 h, and were also substantially less pain
tolerant than controls at both 0 and 3 h. There were no significant
differences in pain detection values between the two groups at 3 h.
Pain tolerance to pain detection ratios for methadone patients were
significantly lower than controls for the cold pressor test at 0 and
3 h, and for electrical stimulation at 0 h only. In summary, the
relative pain sensitivity of methadone maintenance patients is
determined by the nature of the nociceptive stimulus (e.g. cold
pressor test versus electrical stimulation), the plasma methadone
concentration (trough versus peak plasma concentration), and whether
thresholds are determined for detection of pain or pain tolerance.
Although responding to changes in plasma methadone concentration,
maintenance patients are markedly hyperalgesic to pain induced by
the cold pressor test

Reference 6:

Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling
W Department of Clinical and Experimental Pharmacology, Adelaide
University, Adelaide, SA 5005, Australia.


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

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

Reference 7:

Compton P, Charuvastra VC, Ling W School of Nursing, University of
California at Los Angeles (UCLA), Factor Building 4-246, Box 956918,
Los Angeles, CA 90095-6918, USA.

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

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


See also: "Opiate rotation, incomplete cross-tolerance, and hyperalgesic metabolites"


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Alexander DeLuca, M.D., FASAM.

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Originally posted:  10/26/2001

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