A preclinical comparison between different opioids: antinociceptive versus adverse effects

https://doi.org/10.1016/j.pbb.2004.12.002Get rights and content

Abstract

Reduced side-effect liability of opioids may enhance the patients quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO2 was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance.

ED50's for the occurrence of side-effects were compared to ED50's in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED50's. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.

Introduction

Opiates can induce a highly selective alteration in the response of humans and animals to strong and otherwise aversive chemical, mechanical or thermal stimuli. This antinociceptive effect is mediated by opioid receptors, as it is characterized by a structure–activity relationship and the possibility to antagonize these effects (Yaksh, 1997). The clinical choice of an opioid compound depends upon the duration and severity of pain, the route of administration, the desired speed of onset and duration of action, and the adverse effect profile (Bowdle, 1998). There is an enormous variation in the spectrum and severity of opioid adverse effects, dependent on the chemical structure, physiochemical properties and kinetic distribution of the opioid compounds (Meert, 1996), and the dose, route and speed of administration (McQuay, 1999). Opioid-induced side-effects occur in different systems such as the gastrointestinal tract where constipation, nausea and vomiting can be observed, the respiratory system which is depressed, and the central nervous system leading among others to abuse potential (Schug et al., 1992). Adverse effects of opioids are multiple, most often opioid receptor-mediated and therefore almost inseparable from their desired analgesic effects (Schug et al., 1992). The importance of side-effect profiling of opioid compounds can be illustrated by the definition of opioid-insensitive pain, which is pain that does not respond progressively to increasing opioid dose. This insensitivity is usually relative, but increasing the opioid dose to an analgesic effect provokes intolerable or under manageable adverse effects (McQuay, 1999). It has been stated that any opioid that produces fewer adverse effects than morphine at a dose, which provides the same degree of analgesia, would be an improvement (McQuay, 1999) since it would significantly enhance the quality of life of patients (Schug et al., 1992). Unfortunately, selection of the most suitable opioid for a particular patient is difficult since in literature for most clinically important adverse effects there are no comparative data between different opioid compounds at equianalgesic doses. The key factor for comparison is equianalgesic dosing, differences in occurrence of opioid receptor-mediated side-effects may then be explained by differences in receptor binding, distribution and metabolism (McQuay, 1999).

In the present study different opioids used in clinical settings were compared at equianalgesic doses in rats for their side-effect profiles in different organ systems. Similarities in opioid pharmacology and function between species provide a validating support for the conclusion that animal models reveal mechanisms of processing that are present in the human (Yaksh, 1997). Therefore the data of the present study add important information to the knowledge on some opioid compounds that are frequently used in clinical settings. The opioids that have been evaluated are morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone. To analyse the analgesic efficacy of these drugs, a tail withdrawal test was done for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test in an inflammatory model for mechanical hypersensitivity. Several tests were performed for side-effect profiling. To evaluate the inhibition of gastrointestinal activity a charcoal and ricinus oil test were performed, arterial blood was analysed for PaCO2 to evaluate respiratory depression, a drug discrimination learning test was done to determine the discriminative stimulus property linked to abuse potential, and rotarod performance was tested for opioid effect on motor coordination.

Section snippets

Animals

Male Sprague–Dawley rats (Harlan, Eystrup, Germany) weighing 220–240 g were maintained in a climate-controlled environment on a 12 h light/dark cycle at a temperature of 22±1 °C. All experiments were carried out during the light phase. During housing water and food were available ad libitum. Before each experiment animals were starved overnight, tap water remained available ad libitum except during the test period. The animals were habituated to the experimental room for at least 1 h before the

Antinociceptive activities of opioids in the tail withdrawal test

Saline treated animals exhibited mean latencies of 3.30±0.98 s at the various post-injection time points. After sc administration most opioids resulted in a dose-dependent increase in tail withdrawal latencies (Fig. 2). Buprenorphine had a characteristic dose-response curve with a ceiling in analgesic effect at a dose of 2.5 mg/kg, never reaching maximal analgesia, and a decrease in effect at the higher doses of 10–80 mg/kg. The onset of blockade of tail withdrawal occurred fastest for

Discussion

The aim of the study was to compare different opioids for analgesic efficacy and more specifically for side-effect profiling at equianalgesic doses. It was determined whether for a certain opioid compound the occurrence of side-effects is inherent to its analgesic activity, and more important if side-effects occurred when the different compounds were given at a dose that produced a comparable analgesic effect. To establish the analgesic efficacy of the opioid compounds, different behavioural

Acknowledgements

The authors wish to thank R. Biermans, P. De Haes and F. Geenen for their excellent technical support.

References (56)

  • C. Jordan

    Assessment of the effect of drugs on respiration

    Br. J. Anaesth.

    (1982)
  • J. Lorenz et al.

    Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain

    Pain

    (1997)
  • H. McQuay

    Opioids in pain management

    Lancet

    (1999)
  • M.P. Morin-Surun et al.

    Different effects of mu and delta opiate agonists on respiration

    Eur. J. Pharmacol.

    (1984)
  • R. Portenoy

    Opioid therapy for chronic non-malignant pain: a review of the critical issues

    J. Pain Symptom Manage.

    (1996)
  • R. Sabatowski et al.

    Driving ability under long-term treatment with transdermal fentanyl

    J. Pain Symptom Manage.

    (2003)
  • C. Stein et al.

    Unilateral inflammation of the hind paw in rats as a model of prolonged noxious stimulation: alterations in behaviour and nociceptive thresholds

    Pharmacol. Biochem. Behav.

    (1988)
  • A. Vainio et al.

    Driving ability in cancer patients receiving long-term morphine analgesia

    Lancet

    (1995)
  • M.B. Weinger et al.

    A role for CNS a2—adrenergic receptors in opiate-induced muscle rigidity in the rat

    Brain Res.

    (1995)
  • J. Zacny et al.

    College on problems of drug dependence taskforce on prescription opioid non-medical use and abuse: position statement *1

    Drug Alcohol Depend.

    (2003)
  • S.J. Ackerman et al.

    Risk of constipation in patients prescribed fentanyl transdermal system or oxycodone controlled release in a California Medicaid population: abstract

    J. Am. Geriatr. Soc.

    (2003)
  • T.A. Bowdle

    Adverse effects of opioid agonists and agonist–antagonists in anaesthesia

    Drug Safety

    (1998)
  • H. Breivik

    Opioids in cancer and chronic non-cancer pain therapy—indications and controversies

    Acta Anaesthesiol. Scand.

    (2003)
  • N.I. Cherny et al.

    Practical issues in the management of cancer pain

  • F.C. Colpaert et al.

    On the narcotic cuing action of fentanyl and other narcotic drugs

    Arch. Int. Pharmacodyn. Ther.

    (1975)
  • F.C. Colpaert et al.

    Investigations on drug produced and subjectively experienced discriminative stimuli

    Life Sci.

    (1975)
  • J.E. Dum et al.

    In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions

    Br. J. Pharmacol.

    (1981)
  • J.M. Hambrook et al.

    The interaction of buprenorphine with the opiate receptor: lipophilicity as a determining factor in drug receptor kinetics

  • Cited by (93)

    • Anesthesia and analgesia in laboratory rodents

      2023, Anesthesia and Analgesia in Laboratory Animals
    • Treatment of Pain in Rats, Mice, and Prairie Dogs

      2023, Veterinary Clinics of North America - Exotic Animal Practice
    • Rodents

      2022, Carpenter's Exotic Animal Formulary, Sixth Edition
    • Handbook on Opium: History and Basis of Opioids in Therapeutics

      2022, Handbook on Opium: History and Basis of Opioids in Therapeutics
    • Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression

      2021, Life Sciences
      Citation Excerpt :

      Rats were then assigned randomly in one of the 4 groups (n = 6–7): all vehicles; morphine (2, 5, or 10 mg/kg) + vehicles; AMD3100 + maraviroc + vehicle; or morphine (2, 5, or 10 mg/kg) + AMD3100 + maraviroc. Morphine doses were chosen based on previous studies for respiratory depression and antinociception effects [25,26]. Following drug administration, rats were placed in the observation boxes and recordings were started.

    • Mouse model demonstrates strain differences in susceptibility to opioid side effects

      2018, Neuroscience Letters
      Citation Excerpt :

      Thus, the net result of opioid action on the pre-Botzinger-RTN/pFRG complex is an irregular breathing pattern through skipped and prolonged inspiratory periods [31,40]. This acts to prolong the average time per breath cycle, decreasing the breathing frequency [2,4,8]. Although the pre-Botzinger complex has not yet been identified in humans, likely a similar, if not relatively identical, center exists in the human medulla [21,22].

    View all citing articles on Scopus
    View full text