An overview of analgesics: opioids, tramadol, and tapentadol (Part 2)

Pain can be caused by several mechanisms, and the development of chronic pain (also known as pain chronification) is a complex and often unpredictable process. Opioids, tramadol, and tapentadol provide pharmacological solutions to chronic pain of cancer or non-cancer origins, particularly if central sensitization is present. It may also be indicated for short-term use in acute pain. Despite large studies and meta-analyses of opioids for a variety of pain conditions, the evidence for its clinical effectiveness is still unclear. This is, however, mostly due to significant heterogeneity and bias between studies assessed. The dual analgesic mechanisms of tramadol and tapentadol appear to be effective options for pain relief, with an overall lower incidence of opioid-related adverse effects. Tapentadol has an analgesic effect comparable to the strong opioids, which appears to be mediated by its greater mu opioid receptor activity and more selective noradrenaline reuptake inhibition. Tramadol produces less analgesia than tapentadol, but it is also associated with reduced opioid-related adverse effects and dependence. The opioids and tramadol may be significantly affected by polymorphisms of CYP2D6, while this effect is lessened with tapentadol.


Introduction
Part 1 of this series discussed NSAIDs, paracetamol, and topical analgesics as the treatment classes of choice for mildto-moderate pain.Moderate-to-severe pain necessitates consideration of multimodal analgesia, and the use of opioids in this setting may be necessary.Part 2 will discuss the opioid class of drugs, as well as drugs that modulate neurotransmitters in addition to opioid-activity (tramadol and tapentadol).
Pain is a complex and distinctive experience.It includes several pathways, involving nociceptive signal generation (transduction) and propagation (transmission), as well as perception and modulation of the nociceptive stimuli. 1 Pain can been classified according to several approaches, [2][3][4] including: acute, chronic, or breakthrough; cancer or non-cancer; nociceptive, neuropathic, or mixed; or according to intensity (mild, moderate, severe).Of these, acute or chronic pain is probably the most commonly assigned classification.Acute and chronic pain were previously seen as separate entities, and delineated according to duration. 5,6owever, better understanding of the complexity of pain is expanding and questioning this simplified distinction. 7Acute pain is seen as an accepted part of life, and serves as a protective function to prevent further injury and promote tissue healing. 8hronic pain was previously defined as lasting more than 6 months, 6 but has been amended to "pain that lasts beyond the healing of injured tissue and the related inflammatory processes". 8hronic pain has a significant impact on quality of life 9 and places a significant burden on both patients and the healthcare sector. 10 While acute pain was previously seen as distinct from chronic pain, it is now recognised that the transition of acute to chronic pain (termed pain chronification) may actually be a continuum, 11 and that the underlying mechanisms of pain may be more important than duration in its development. 5e mechanisms of pain chronification are not fully understood, and risk factors for its development remain unclear.Proposed mechanisms involve sensitization of nociceptive neurons, and these may be present peripherally and/or centrally. 5Peripheral sensitization appears to be induced by persistent stimulation of primary afferent nociceptive neurons leading to neuroplastic changes of the nerves. 12These changes confer increased responsiveness 6 and protracted hypersensitivity of peripheral nociceptive neurons (termed "hyperalgesic priming"), 13 and constitutes the development of primary hyperalgesia, which leads to steady stimulation of the secondary afferent neurons in the dorsal horn, and may result in secondary hyperalgesia and the development of central sensitization. 14This, however, does not fully explain why only some patients with peripheral and/ or central sensitization develop chronic pain.Consequently, pain chronification seems to involve other processes as well, such as changes in pain modulation, neuroplasticity, and pain perception (neuromatrix). 5ronic pain is therefore multifactorial in origin, and involves multiple sites in the nervous system.This is the rationale for multimodal analgesia, 15 and can be applied to both acute and chronic pain.Pain management was previously approached with substantial reference to the World Health Organization (WHO) analgesic ladder. 16The recommended escalation of analgesia by adding increasingly potent opioid drug classes to non-opioids was developed for cancer pain, but has subsequently also been applied to non-cancer pain.While this stepwise approach may provide a good foundation for universal access to analgesia, The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd17 it leaves some gaps, specifically that adequate analgesia is not achieved in many patients, 17 and that newer analgesic techniques (such as neuraxial procedures) are not incorporated.This in turn may contribute to the development of chronic pain.A new, bidirectional ladder has therefore been proposed to address acute pain adequately, and to optimise the management of chronic pain. 18It makes provision for both cancer and noncancer pain, and provides a "start high-step down" approach for acute pain, and a "start low-step up" approach for chronic pain (Figure 1).

Mechanism of action
The opioids comprise a diverse range of naturally occurring, semi-synthetic or synthetic compounds.These drugs have varying degrees of potency and can act as agonists (e.g.morphine, oxycodone, hydromorphone, codeine), partial agonists (e.g.buprenorphine), or antagonists (e.g.naloxone) at the opioid receptors. 19The opioid receptors are classified as mu, kappa, and delta, and revision by the International Union of Pharmacology (IUPHAR) in 2000 expanded the names to include the interchangeable terms MOP (mu opioid peptide), KOP (kappa opioid peptide) and DOP (delta opioid peptide) receptors. 20A fourth receptor NOP (nociceptin opioid peptide) was later discovered, but its significance is currently not well defined. 20e analgesic effects of the opioid agonists are largely mediated by activation of the mu receptors.This activation is also responsible for most of the adverse effects related to opioid use, and includes sedation, respiratory depression, nausea, and vomiting. 19Opioid-mediated analgesia originates primarily in the central nervous system, 1,15,19 where it stimulates descending inhibition in the midbrain with the downstream effect of attenuating ascending nociceptive signals in the dorsal horn of the spinal cord (Figure 2).Opioids also stimulate dorsal horn nerve fibres and other peripheral nociceptors directly, further attenuating ascending signals. 21The central analgesic effects of opioids also appear to be mediated by modulation of pain perception within the neuromatrix.
Clinical responses to opioids vary and may be related to the type of pain, medical conditions, concomitant drugs, and patient metabolizer status. 23Metabolizer status may account for unexpected responses to opioids, but are difficult to predict as most opioids have complex metabolic pathways with varying degrees of active and inactive metabolites. 23A classic example is codeine, which exerts the primary analgesic effect via its metabolism to morphine that has a 200 times greater affinity for the mu receptor than codeine itself. 24This biotransformation is mediated by cytochrome P450 (CYP) 2D6 enzymes, and the gene encoding these enzymes is highly polymorphic. 25Consequently, based on CYP2D6 enzyme activity, patients can be classified as either poor, extensive, or ultrarapid metabolizers.Poor metabolizers are not able to readily convert codeine to morphine, and may therefore not achieve adequate analgesia. 24Conversely, ultrarapid metabolizers may generate toxic concentrations of morphine and, following several case reports of this effect, the American Food and Drug Administration (FDA) released a safety announcement restricting its use in children and breastfeeding mothers. 26The prevalence of CYP2D6 poor and ultrarapid metabolizers in the general population is estimated to be 5-10% and 1-2%, respectively. 25armacogenetic factors may explain some of the interindividual variation of opioid effects, but even after correcting for these and various other factors, individual responses still vary.Molecular studies have identified different mu receptor subtypes, and have suggested that this variability may be due to differential functional activation by opioids, as well as the receptor subtype localizations in the body. 27

Place in therapy: Cancer pain
The management of cancer pain is universally recommended to include a multimodal approach, 28 encompassing not only multiple pharmacological modalities (if needed), but also including patient education and social structure support.[31][32] Table 1: Summarized recommendations for opioid use in cancer pain management Patient-specific goals for pain management need to be considered, and the undertreatment of pain prevented.
Persisting or new pain requires comprehensive assessment for possible cause, identification of a pain syndrome, and patient goals.
Oral analgesics are preferred, but pain that requires urgent relief may be managed with parenteral opioids.The use of modified-release opioids for acute pain is discouraged.
In mild to moderate pain not controlled by NSAIDs, a weak oral opioid (codeine or tramadol) may be added according to the WHO analgesic ladder.
In moderate to severe pain strong opioids may be added, but there is no preference between morphine, oxycodone, and hydromorphone.
Switching between different opioids is frequently done in practice for inadequate pain relief or severe adverse effects, but is not supported by strong evidence.
For maintenance analgesia, regular doses of opioids are recommended, with rescue doses as needed.The management of adverse effects (e.g.constipation), and support structures for patients and families are also strongly advocated.
NSAIDs: Nonsteroidal anti-inflammatory drugs.WHO: World Health Organization The effectiveness and safety of opioids for cancer pain was assessed in a 2017 systematic review of nine previously conducted systematic reviews, and included around 120 studies. 33The authors state that the effectiveness of opioids for cancer pain was difficult to interpret due to significant heterogeneity of the studies.However, given extensive clinical experience and the available data, they concluded that for pooled effects of the different opioids, around 95% of patients with moderate or severe pain who are given opioids -and can tolerate these -should have their pain reduced to mild or no pain within 2 weeks.The review also found that most patients will experience opioid-related adverse effects, and that 10-20% of these patients will find the adverse effects intolerable, leading to a change in treatment.Of note is that the effectiveness and safety of opioids in these studies were evaluated over a short period of time (weeks).A recent article addressed this lack of evidence of long-term opioid use in cancer pain and highlighted the need for more robust data. 34The current opioid epidemic that started in the late 1990s 35 has highlighted the risk of opioid dependence, and concern for dependence in the cancer population has been expressed. 36However, the 2015 American National Survey on Drug Use and Health 37 surveyed the use of prescription opioids and found that a higher prevalence of prescription opioid use without misuse was present in those with cancer compared to those without cancer (93.9% vs 87.0%).Cancer patients also had a lower prevalence of opioid misuse without use disorders (5.3% vs 10.8%) and opioid use disorders (0.8% vs 2.2%) compared to those without cancer.

Place in therapy: Non-cancer pain
The role of opioids for cancer pain is clearly defined, but the risks and benefits of opioids in acute and chronic non-cancer pain is less well established.Opioids for acute pain are frequently prescribed in the postoperative period, emergency department, and primary care setting. 38While opioids can be very effective in these environments, the current opioid epidemic has illuminated how injudicious use of opioids in the acute setting may lead to chronic use and dependence.It is therefore prudent to use opioids selectively for acute pain from the choice of available analgesics.General principles relating to acute opioid prescriptions are to use opioids only for moderate to severe pain at the lowest effective dose for the shortest possible duration, the use of immediate-release formulations of opioids, and to consider multimodal, opioid-sparing management where applicable. 32,392018 systematic review and meta-analysis 40 of 96 randomised controlled trials assessed opioids for chronic non-cancer pain, and included studies of neuropathic pain, nociceptive pain, mixed pain, and central sensitization (defined as pain that is present in the absence of tissue damage).The review found an overall small improvement in pain and physical functioning, but this did not reach clinical significance.An increased risk of vomiting, compared with placebo, was also found.Another systematic review and meta-analysis assessed the evidence of opioids for neuropathic pain. 41The findings showed significant efficacy over placebo, although small sample size and short study The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd19 duration likely introduced significant bias.The comparison of opioids to placebo for neuropathic pain also does not reflect best current practice, as other drugs (such as the anti-epileptics and antidepressants) have shown superior efficacy for neuropathic pain.The use of these and other drugs in neuropathic pain, as well as the proposed pathophysiological mechanisms, will be discussed in Part 3 of this series.Further systematic reviews assessing opioids for osteoarthritis of the knee or hip, 42 or for chronic low-back pain, 43 found corresponding results: opioids may have a small benefit for pain relief, but low quality studies and significant increases in adverse effects limit its interpretation and significance.

Mechanism of action
Tramadol is a centrally acting atypical opioid, as it has both opioid and neurotransmitter reuptake inhibition activity contributing additively to its analgesic effect. 44Tramadol is peculiar in that the analgesia produced by mu opioid receptor stimulation is primarily due to an active metabolite (M1) generated by the CYP2D6 enzyme, [44][45][46] whereas the parent drug -while having some opioid receptor activity -is largely responsible for neurotransmitter reuptake inhibition. 47Tramadol is metabolized to over 20 metabolites, but only M1 as an active metabolite is regarded as significant. 48amadol is a racemic mixture of (+) tramadol and (-) tramadol, with the (+) enantiomer forming the active M1 metabolite. 44he (+) enantiomer is also thought to be primarily responsible for serotonin reuptake inhibition, 49 while the (-) enantiomer appears to largely mediate noradrenaline reuptake inhibition. 50his inhibition of serotonin and noradrenaline reuptake is thought to enhance descending inhibition pathways in the spinal cord, 44 while opioid receptor agonism produces analgesia by mechanisms described earlier (Figure 2).The dual analgesic mechanism of tramadol is further suggested by evidence that naloxone, an opioid antagonist, only partially reverses tramadol's analgesic effect. 51

Place in therapy
The potency of parenteral tramadol compared to morphine is in the range of 10%.Oral tramadol has a higher bioavailability than oral morphine, and its potency is estimated to be about 20% of morphine. 52Tramadol appears to be equipotent to codeine at therapeutic doses. 44,52Tramadol does, however, have significant inter-individual variability of efficacy and adverse effects. 53This may be related to CYP2D6 polymorphisms, with poor metabolizers at an increased risk for inadequate analgesic response, 54 and extensive or ultrarapid metabolizers possibly experiencing more adverse effects. 53Drugs that are inhibitors or inducers of CYP2D6 may also contribute to the wide variability. 55ausea and dizziness are frequent adverse effects of tramadol, 52 but its effect on respiratory depression, as well as dependence and abuse potentials, are low compared to morphine. 56Of note is that tramadol appears to lower the seizure threshold, and the risk of seizure is increased with concomitant use of other seizure threshold-lowering drugs. 57The increase in serotonin induced by tramadol may theoretically cause serotonin syndrome, but this is rarely seen with tramadol as monotherapy, and occurs in practice when other enhancers of serotonin are co-administered. 58amadol is frequently used to treat acute and chronic pain.For cancer pain management it is part of step 2 of the WHO analgesic ladder. 16The efficacy of tramadol for moderate to severe acute pain has been well described, 59,60 and the addition of non-opioid analgesics (such as paracetamol or an NSAID) appears to potentiate its effects. 61,62Several systematic reviews have assessed the efficacy of tramadol in chronic pain conditions including osteoarthritis, 63 neuropathic pain, 64 and cancer pain. 65 small beneficial effect of tramadol was noted in the analyses of these conditions, but its interpretation and application in clinical practice is limited by low quality evidence, and significant heterogeneity and small sample sizes of the studies.

Mechanism of action
Tapentadol is a new generation atypical opioid that was recently registered in South Africa as a non-racemic, schedule 6 medication.Its design was based on the additive dual mu opioid receptor and neurotransmitter reuptake inhibition mechanism of tramadol, but with greater focus on noradrenaline than serotonin reuptake inhibition. 667][68] In animal models, noradrenaline reuptake inhibition appears to be particularly significant to the attenuation of neuropathic pain. 69apentadol is an active drug and, contrary to tramadol, its dual activity is not dependant on metabolism to active metabolites for its analgesic effect. 55Polymorphisms of CYP2D6, as well as drugs that are inhibitors or inducers of CYP2D6, are therefore not expected to cause significant inter-individual variability. 55

Place in therapy
Tapentadol is only available as an oral formulation, and its analgesic potency compared to morphine is estimated to be around 40%. 70 This translates to a significant relative increase in the analgesic effect compared to tramadol, but clinically tapentadol is compared to oxycodone, hydromorphone, and morphine. 71There is a paucity of data of head-to-head studies comparing tapentadol to tramadol, and this appears to be due to tapentadol's increased analgesic effect leading to comparisons to strong opioid drugs.The potentiated analgesia attained appears to be due to tapentadol's increased mu opioid receptor activity, more potent inhibition of noradrenergic reuptake, and a synergistic -rather than additive -combined effect. 72Clinical and post-marketing studies have found that tapentadol has less opioid-related adverse effects compared to the strong opioids, 71 but the prevalence compared to tramadol still is significantly more. 73pentadol has shown favourable efficacy to the strong opioids, 71,74,75 but this mostly relates to chronic or recurrent pain (cancer and non-cancer), and may be overstated when subjected to systematic reviews. 76,77Tapentadol also has selected advantages over the strong opioids, including lower risk of dependence and abuse potential, less opioid-related adverse effects, and low risk of pharmacokinetic drug interactions. 66,71,74,75,78,79

Summary
Analgesia for moderate-to-severe pain may require the use of opioids, tramadol, or tapentadol.Comprehensive management of chronic pain may need a multimodal approach, as the underlying processes that drive pain chronification appear to be more complex and poorly localized.The evidence for the recommendation of opioids in cancer and non-cancer pain is limited by heterogeneity of studies and frequent adverse effects, but clinical experience indicates that opioids are effective for moderate-to-severe pain.Opioid dependence is a global concern, but current evidence indicates that opioid use for cancer pain is effective without a significant risk of dependence.Tramadol and tapentadol are newer, atypical opioids that are mu receptor agonists as well as neurotransmitter reuptake inhibitors.Tramadol exerts both serotonin and noradrenaline reuptake inhibition in addition to opioid activity, but adverse effects of nausea and dizziness are frequent.Tapentadol has increased analgesic effects compared to tramadol.This appears to be mediated by tapentadol's more potent opioid activity and more selective noradrenergic reuptake inhibition, subsequently making it comparable to the strong opioids.Tapentadol has less opioid-related adverse effects and dependence compared to the strong opioids, but these effects are still significantly more compared to tramadol.For drugs that are metabolized to an active form (such as tramadol or codeine), metabolizer status may significantly impact the effectiveness and safety of these drugs.