The Importance of Opioid Tolerance: A Therapeutic Paradox

Thompson, A. Reed; Ray, James

doi:10.1016/s1072-7515(02)01800-8

Cited by 22 publications

(12 citation statements)

References 15 publications

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“…Upon repeated administration, tolerance develops to many of its effects including analgesia, nausea, vomiting and respiratory depression (Thompson and Ray, 2003). However, clinical evidence suggests that tolerance does not develop to morphine-induced constipation which limits the chronic use of this excellent pain reliever in man (Ling et al, 1989; Yuan et al, 1998; Thompson and Ray, 2003; Gutstein and Akil, 2006). Indeed, many terminally ill patients choose to discontinue opioid treatment to alleviate the discomfort of chronic opioid-induced bowel dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Morphine Tolerance in the Mouse Ileum and Colon

Ross¹,

Gabra²,

Dewey³

et al. 2008

J Pharmacol Exp Ther

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Repeated administration of morphine is associated with tolerance to its antinociceptive properties. However, constipation remains the major side effect of chronic exposure to morphine. In contrast, previous studies suggest that tolerance to opioids develops in the ileum of several species. In this study, we provide evidence that constipation may arise due to a lack of tolerance development to morphine in the colon. Mice received implants with either placebo or 75 mg of morphine pellets, and they were examined for morphine tolerance to antinociception, defecation, and intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon, and contractile responses were measured from longitudinal and circular muscle preparations. In morphine-pelleted mice, a 5.5-fold tolerance developed to antinociception after 72 h, and a 53.2-fold tolerance developed in mice that received an additional daily morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscles, electrical field stimulation-induced cholinergic contractions were dose-dependently inhibited by morphine in both the ileum and colon of placebo pelleted with a pD 2 of 7.1 Ϯ 0.4 and 7.8 Ϯ 0.4, respectively. However, the dose response to morphine inhibition was shifted to the right for the ileum from morphine-pelleted mice (pD 2 ϭ 5.1 Ϯ 0.4) but not the colon (pD 2 ϭ 6.9 Ϯ 0.4). In circular muscle preparations, morphine induced atropine-insensitive contractions in both tissue segments. Tolerance to morphine developed in the ileum but not the colon upon repeated administration of morphine. These findings indicate that a lack of tolerance development in the colon is the basis for opioid bowel dysfunction.

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Section: Introductionmentioning

confidence: 99%

Morphine Tolerance in the Mouse Ileum and Colon

Ross¹,

Gabra²,

Dewey³

et al. 2008

J Pharmacol Exp Ther

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“…[4][5][6] Tolerance commonly develops to opioids on long-term use, requiring increased doses to achieve the same analgesia. 7 Although some tolerance develops to the effects of opioids on gastrointestinal motility, constipation often persists unless remedial measures are taken. 8 Few published reports compare the constipating effects of the various opioid analgesics or evaluate the opioid-related adverse effects associated with specific routes of administration.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Morphine Can Avoid Distressing Constipation Associated With Oral Morphine: A Retrospective Analysis of Our Experience in 11 Patients in the Palliative Care In-Patient Unit

Mazumdar

Mishra

Bhatnagar

et al. 2008

Am J Hosp Palliat Care

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Morphine is the preferred strong opioid analgesic. Most of the adverse effects, such as daytime drowsiness, dizziness, mental clouding, and effects on cognitive and psychomotor function or nausea and vomiting, usually resolve with time. The main continuing adverse effect of morphine is constipation, and prophylactic use of laxative is almost always required. We are presenting retrospective data of 11 patients admitted in our palliative care unit over the past 5 months for new (not yet received any opioid analgesic in any form) and severe cancer pain management. It was found that none of the patients was having constipation with intravenous morphine. This finding can be explained on the basis of differences in pharmacologic profiles, in affinity to opioid receptor, and a higher exposure of opioid-binding receptor in the GI tract after oral administration of morphine compared with intravenous morphine. This explanation was further affirmed as constipation and need for laxative was reported by 7 of the 11 patients when they were given the equi-analgesic oral doses of morphine. Thus, the route of administration seems to be responsible for the above finding; hence, further evaluation with prospective observation and data collection is being planned to look for external validity in a larger population catered by our palliative care unit.

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“…The dose of opioids that induces constipation is much smaller than that required for analgesia; thus, using lower doses of opioids will not prevent constipation. With repeated exposure to morphine, tolerance does not develop to constipation as it does to other effects such as analgesia [Ling et al, 1989;Thompson and Ray, 2003]. Tolerance development may be linked to the existence of subtypes of mu receptors that mediate various pharmacological actions [Ling et al, 1989;Pasternak, 2001].…”

Section: Constipationmentioning

confidence: 99%

Development and use of methylnaltrexone, a peripherally acting opioid antagonist, to treat side effects related to opioid use

Yuan

Foss

Williams

et al. 2009

Drug Development Research

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Opioid medications are used extensively as potent analgesics for treating moderate to severe pain. Although opioids offer reliable pain relief, their use is associated with a number of adverse effects, especially constipation. Conventional measures for ameliorating opioid-induced adverse effects are often insufficient. Thus, reducing the severity of these adverse effects is of utmost importance for patients who require the benefits of opioid analgesics. Since opioids mediate pain-relieving and adverse effects through the same classes of receptors, i.e., mu, delta, and kappa, it has been challenging to dissociate beneficial effects from detrimental ones. Methylnaltrexone is the first peripherally acting opioid receptor antagonist to receive FDA approval. This compound offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating opioid withdrawal symptoms, which are mediated predominantly by receptors in the central nervous system. This review provides a history of the development of methylnaltrexone, discusses studies that relate to opioid bowel dysfunction, and explores other uses of this compound. Drug Dev Res 70 : 403-416, 2009.

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The Importance of Opioid Tolerance: A Therapeutic Paradox

Cited by 22 publications

References 15 publications

Morphine Tolerance in the Mouse Ileum and Colon

Morphine Tolerance in the Mouse Ileum and Colon

Intravenous Morphine Can Avoid Distressing Constipation Associated With Oral Morphine: A Retrospective Analysis of Our Experience in 11 Patients in the Palliative Care In-Patient Unit

Development and use of methylnaltrexone, a peripherally acting opioid antagonist, to treat side effects related to opioid use

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