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Tramadol is a centrally acting analgesic in widespread use throughout the world. Although there is extensive preclinical, clinical, post-marketing and epidemiological data indicating relatively low--but not zero--abuse/dependence, questions continue to arise about its abuse potential and appropriate regulatory classification. This article considers these questions from the point of view of the basic pharmacology of tramadol. There is nothing unique about tramadol in this regard, but its multimodal mechanism of action, pharmacologically active enantiomers, and active metabolite make it a particularly instructive and relevant example.

Although tramadol is one of the most widely used centrally acting analgesics worldwide, no literature is available regarding adsorption of tramadol HCl powder or tablets (Ultram; 50 mg tramadol HCl per tablet) by activated charcoal (AC) for use as potential adjunct treatment of overdose. The present study incorporated a novel combination of in vitro and in vivo methods to investigate this question. Based on a binding curve of tramadol UV absorbance (UV(a); 225 nm) plotted against the amount of AC, the ratio of amount of tramadol completely adsorbed by AC was 0.05 mg/mg. Also based on UV(a), no tramadol was detected in filtrate of slurries in which up to 62 tablets of Ultram were mixed with 50 g AC; 4.6% of unbound tramadol was detected when 100 tablets of Ultram were mixed with AC. The ratio of amount of tramadol completely adsorbed by AC in this test was 0.10. In vivo, co-administration of 0.1 g/ml of AC produced a 13- to 14-fold rightward shift in tramadol's antinociceptive dose-response curve and a 1.6-fold rightward shift in tramadol's lethality dose-response curve.

Summary: What is known and objective: Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach—indirect enhancement of endogenous pain‐relieving pathways—might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs). Methods: Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents. Results: Inhibition of the enzymes that degrade the endogenous opioid ligands Met‐ and Leu‐enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin‐degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual‐acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs. What is new and conclusion: Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more “natural” and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are “multimechanistic”) and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more‐modern analgesics combine opioid and non‐opioid mechanisms, and have become known as “atypical opioids.” Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. Comment: Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non‐opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. What is new and conclusion: As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non‐opioid properties. Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines—Nature's “atypical opioids.” [ABSTRACT FROM AUTHOR]

What is known and objective Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide ( NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol. Methods Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for cebranopadol in particular. The identified sources were reviewed and the information synthesized. Results The preclinical testing of cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. What is new and conclusion Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

What is known and objective Opioid-induced constipation ( OIC) is one of the most common opioid-induced adverse effects. Pregnancy also predisposes to bowel dysfunctions due to the associated endocrine changes. Pregnant women are thus at greater risk of OIC. We review the non-pharmacologic and pharmacologic treatment options as a guide for achieving a clinically optimal strategy for the management of OIC during pregnancy. Methods The published literature was searched for current therapeutic options, including non-pharmacologic dietary modifications, laxatives, and the peripherally acting mu-opioid receptor antagonists ( PAMORAs). Each was assessed for efficacy and safety, particularly as they relate to pregnancy. Results and discussion Non-pharmacologic approaches such as dietary change are generally safe, but generally insufficient when used alone to control OIC in pregnancy. Laxatives (bulking, osmotic, stimulant) can be effective, but have potential adverse effects that might be particularly troublesome during pregnancy (e.g. electrolyte disturbances, dehydration, abdominal pain, and pulmonary oedema or hypermagnesaemia in the extreme). PAMORAs, which attenuate OIC without affecting opioid-induced analgesia, have been associated with only minimal side effects during the clinical studies to date. What is new and conclusions Conventional non-pharmacologic and pharmacologic options for the management of OIC in pregnancy are often suboptimal due to insufficient efficacy or adverse effects particularly troublesome during pregnancy. The PAMORA strategy appears to provide a safe and effective new option superior to conventional therapies for the management of OIC during pregnancy. [ABSTRACT FROM AUTHOR]

What is known and objective The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators - thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes ( PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor ( DOR). We present a concise update on the status of progress and opportunities of this approach. Methods A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from . Results and discussion DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. [ABSTRACT FROM AUTHOR]

Summary What is known and Objective: The phenomenon of opioid-induced hyperalgesia (OIH), an increased sensitivity to pain attributed to the very opioid drugs administered to manage the pain, is well established in animal models, and there is concern that it also occurs in patients. Our objective is to briefly summarize the basic science and clinical evidence about OIH as background to consider the possible benefit of using a multi-mechanistic analgesic approach. Comment: It is unclear how OIH occurs, or even why; presumably, it is part of an adaptive response. But development of OIH poses a serious treatment dilemma. OIH differs from tolerance, which also presents as reduced analgesic effect, in that tolerance is addressed by judicious and monitored increase in opioid dose, but OIH would be treated by a decrease in opioid dose. Therefore, it is important to avoid induction of OIH. Currently, it is not clear which patients are at greater risk of developing OIH, or which drugs are at greater risk of producing it. What is new and Conclusion: We suggest that multi-mechanistic analgesia, accomplished within either a single drug or a combination of drugs, is a logical approach that might result in a reduced development of OIH. [ABSTRACT FROM AUTHOR]

What is known and objective The Centers for Disease Control and Prevention ( CDC) have published guidelines for opioid prescribing, with the goal of helping guide clinicians to make safe prescribing choices. In the form of 12 statements, the CDC offers guidance that at times is not supported by the evidence or introduces new concepts (such as a requirement that opioids improve function). Our objective was to examine the new guidelines in terms of how well they could strike the balance between keeping opioids accessible to those who need them while appropriately restricting their use. What is new and conclusion The CDC guidelines offer some reasonable and laudable guidance, but they also make some recommendations which are not supported by current scientific evidence. We also noted that the urgent need for greater education among opioid prescribers was not addressed in the new guidelines. [ABSTRACT FROM AUTHOR]