Full Opioid Agonists and Tramadol: Pharmacological and Clinical Considerations

: Opioids are mu receptor agonists and have been an important part of pain treatment for thousands of years. In order to use these drugs appropriately and successfully in patients, whether to control pain, to treat opiate-induced side effects, or opiate withdrawal syndromes, a solid understanding of the pharmacology of such drugs is crucial. The most recognized full agonist opioids are heroin, morphine, codeine, oxycodone, meperidine, and fentanyl. Phenanthrenes refer to a naturally occurring plant-based compound that includes three or more fused rings. The opioids derived from the opium plant are phenanthrene derivatives, whereas most synthetic opioids are simpler molecules that do not have multiple rings. Methadone acts as a synthetic opioid analgesic similar to morphine in both quality and quantity; however, methadone lasts longer and in oral form, has higher efficacy, and is considered a diphenylheptane. Fentanyl is a strong synthetic phenylpiperdine derivative that exhibits activity as a mu-selective opioid agonist approximately 50 to 100 times more potent than morphine. Meperidine is another medication which is a phenylpiperdine. Tramadol is considered a mixed-mechanism opioid drug, as it is a centrally acting analgesic that exerts its effects via binding mu receptors and blocking the reuptake of monoamines. Some of the most common adverse effects shared among all opioids are nausea, vomiting, pruritus, addiction, respiratory depression, constipation, sphincter of Oddi spasm, and miosis (except in the case of meperidine). Chronic opioid usage has also established a relationship to opioid-induced hypogonadism and adrenal suppression. Physicians must be stewards of opioid use and use opioids only when necessary.

108 Warning: Generic Suboxone Not Equal to Name Brand

Introduction:On June 14, 2018, the FDA approved generic buprenorphine/naloxone, as an alternative to the brand Suboxone (FDA,2018). A patient who developed acute withdrawal symptoms when switched from Suboxone to generic buprenorphine/naloxone at the same dosage, with resolution with replacement with brand name Suboxone, is presented. Induction of withdrawal with generic buprenorphine/naloxone has not heretofore been described.Methods:Case Study: A 39-year-old right handed single male presented with a past medical history of intravenous heroin dependence. He was relapse free for 5 years and without change on Suboxone film 8mg/2mg twice daily, and was provided with prescriptions for the same, which was substituted to generic brand Dr. Reddy’s Lab SA buprenorphine HCl/naloxone HCl 8mg/2mg film. After two days on this, one hour after taking generic buprenorphine/naloxone film, symptoms of withdrawal began as manifest by hot flashes, diaphoresis, cold chills, leg cramping, and nausea without vomiting. These were the same symptoms he experienced during his past inpatient withdrawal from opioids. These symptoms recurred every day for an entire week until switching back to brand name Suboxone, whereupon his withdrawal symptoms resolved.Discussion:The mechanism whereby the generic buprenorphine/naloxone combination induced withdrawal symptoms is unclear. It appears that this generic version was either not effectively blocking the mu receptors or the naloxone was inducing a withdrawal state. Possibly the porous nature of the film was such that less of the buprenorphine was absorbed through the mucosa. As a result, less was transferred into the bloodstream, across the blood brain barrier, to the nucleus accumbens, and ultimately on kappa opioid/mu receptor (Centerwatch, 2002). Alternatively, a greater amount of naloxone may have been absorbed transmucosally, thus inducing withdrawal. The absorption may have been normal, but the exact milligram dosage may not be accurate with either too little buprenorphine or too much naloxone. On the other hand, this buprenorphine compound may have been pH sensitive, such that it became inactivated upon exposure to the mildly acidic salivary pH. He could have been malingering this response. Again this is unlikely since he was not given a higher dose of buprenorphine/naloxone, rather the same dose of Suboxone as previously prescribed. It is important that physicians be aware of the possibility for acute withdrawal and increased cravings, which can lead to relapse while using this agent. Further investigation of the efficacy of the generic variant and Suboxone as replacement therapy is warranted.

Сentral and peripheral mechanisms of mu-opioid analgesia and tolerance

Objective – An analysis of the basic science and clinical publications found in PubMed, Medline, and Web of Science. The search covered modern laboratory and clinical mechanisms of peripheral mu opioid analgesia, the role of peripheral mu receptors in systemic analgesia and the development of tolerance to the analgesic effect of opioids. The review discusses the regulatory mechanisms of synthesis and transport of mu-opioid receptors in the primary afferent neurons and the molecular mechanisms responsible for modulating the conduction of nociceptive information from the periphery to the spinal cord. According to some authors, the peripheral component can account for 50-90% of the total analgesic effect after the systemic administration of morphine and methadone. The review reports on the important role of glycoprotein-P and the blood-brain barrier transport system in modulating the peripheral component of the analgesic effect of morphine as well as the synergistic interaction between central and peripheral mu receptors. The results of the reviewed studies convincingly show the key role of peripheral mu receptors in the development of tolerance to the analgesic effect of morphine after its systemic administration. The mechanisms of opioid tolerance also involve peripheral anti-opioid, pronociceptive systems such as NMDA receptors. It is well known that the same mechanisms are involved in maintaining peripheral hyperalgesia and allodynia. The development of analgesic drugs that act on peripheral antinociceptive systems offers a promising perspective on the possible treatment of acute and chronic pain.

Inhibition of granulocyte ROS production by opioids prevents regeneration

SUMMARYInhibition of regeneration and induction of healing are classic outcomes of tissue repair in adult mammals. Here, by using gain and loss of function experiments, we demonstrate that both endogenous and exogenous opioids prevent tissue regeneration in adults, by inhibiting the early reactive oxygen species (ROS) production occurring after lesion and required for regeneration. These effects can be overcome and regeneration induced by the use of an opioid antagonist. These results, obtained in both gold-standard adult zebrafish and a newly-developed model of regeneration in adult mammals, demonstrate that this mechanism can be considered as a general paradigm in vertebrates. In addition, we show that opioids act via signaling through peripheral mu-receptors expressed on granulocytes. This work clearly demonstrates the deleterious role of opioids on tissue regeneration through the control of ROS production in vertebrates and thus questions about opioid-based analgesia in perioperative care.

Systemic analgesics (including paracetamol and opioids)

Apart from non-steroidal anti-inflammatory drugs (NSAIDs), there are only two categories of systemic analgesics, namely paracetamol (acetaminophen) and opioids, that are currently available worldwide for clinical use. Paracetamol is poorly effective in relieving pain and improving function in patients with symptomatic osteoarthritis (OA). Furthermore, its safety profile is less favourable than classically thought. In fact, there is evidence paracetamol acts as a weak inhibitor of the cyclooxygenase enzymes. Given that paracetamol poses a lower risk of severe adverse events than NSAIDs while being better tolerated than opioids, it is usually considered as the first-line systemic analgesic for OA. Commonly prescribed opioids are primarily agonists of the mu receptors, thereby producing similar desirable (analgesia) and untoward effects. Meta-analyses of short-term clinical trials showed that, on average, the modest clinical benefits of opioids did not outweigh the side effects in patients with knee or hip OA. Accordingly, most current guidelines support the use of opioids for selected OA patients only (e.g. patients who have not had an adequate response to other treatment modalities and are not candidates for total joint arthroplasty). In view of the limited efficacy and/or potential harms of available analgesics, particular attention was paid to novel painkillers, especially nerve growth factor (NGF) antagonists. Although these agents provided clinically meaningful improvements in pain and physical function in patients with hip or knee OA, they lead to severe side effects, including rapidly destructive arthropathies and neuropathies. Thus, if approved for marketing, NGF antagonists would be reserved for selected and well-defined patients with OA.