A preclinical comparison between different opioids: antinociceptive versus adverse effects
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)
- et al.
Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life
J. Pain Symptom Manage.
(1997) Discriminative stimulus properties of narcotic analgesic drugs
Pharmacol. Biochem. Behav.
(1978)- et al.
Prolonged treatment with transdermal fentanyl in neuropathic pain
J. Pain Symptom Manage.
(1998) - et al.
Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain
Pain
(1996) - et al.
The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats
Pain
(1977) Principles of opioid pharmacotherapy: practical implications of basic mechanisms
J. Pain Symptom Manage.
(1996)- et al.
Are opioid-dependent/tolerant patients impaired in driving-related skills? A structured evidence-based review
J. Pain Symptom Manage.
(2003) - et al.
Transdermal fentanyl in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region
Pain
(1997) - et al.
The constipation-inducing potential of morphine and transdermal fentanyl
Eur. J. Pain
(1999) - et al.
Role of opioid receptors in the substantia nigra in morphine induced muscular rigidity
Life Sci.
(1982)
Assessment of the effect of drugs on respiration
Br. J. Anaesth.
Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain
Pain
Opioids in pain management
Lancet
Different effects of mu and delta opiate agonists on respiration
Eur. J. Pharmacol.
Opioid therapy for chronic non-malignant pain: a review of the critical issues
J. Pain Symptom Manage.
Driving ability under long-term treatment with transdermal fentanyl
J. Pain Symptom Manage.
Unilateral inflammation of the hind paw in rats as a model of prolonged noxious stimulation: alterations in behaviour and nociceptive thresholds
Pharmacol. Biochem. Behav.
Driving ability in cancer patients receiving long-term morphine analgesia
Lancet
A role for CNS a2—adrenergic receptors in opiate-induced muscle rigidity in the rat
Brain Res.
College on problems of drug dependence taskforce on prescription opioid non-medical use and abuse: position statement *1
Drug Alcohol Depend.
Risk of constipation in patients prescribed fentanyl transdermal system or oxycodone controlled release in a California Medicaid population: abstract
J. Am. Geriatr. Soc.
Adverse effects of opioid agonists and agonist–antagonists in anaesthesia
Drug Safety
Opioids in cancer and chronic non-cancer pain therapy—indications and controversies
Acta Anaesthesiol. Scand.
Practical issues in the management of cancer pain
On the narcotic cuing action of fentanyl and other narcotic drugs
Arch. Int. Pharmacodyn. Ther.
Investigations on drug produced and subjectively experienced discriminative stimuli
Life Sci.
In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions
Br. J. Pharmacol.
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 AnimalsTreatment of Pain in Rats, Mice, and Prairie Dogs
2023, Veterinary Clinics of North America - Exotic Animal PracticeRodents
2022, Carpenter's Exotic Animal Formulary, Sixth EditionHandbook on Opium: History and Basis of Opioids in Therapeutics
2022, Handbook on Opium: History and Basis of Opioids in TherapeuticsChemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression
2021, Life SciencesCitation 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 LettersCitation 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].