Novel Analgesic Drug Holds New Promise For Chronic Pain Relief

Novel Analgesic Drug Holds New Promise For Chronic Pain Relief

Musculoskeletal conditions are the most common cause of chronic pain and affect roughly one in five adults in Europe, according to a new paper published in Reumatismo — the official journal of the Italian Society of Rheumatology.

The paper, entitled “Chronic pain: the burden of disease — and treatment innovations,” (Reumatismo. 2015 Oct 23;67(2):35-44. DOI: http://dx.doi.org/10.4081/reumatismo.2015.840), is coauthored by S. Monti and R. Caporali of the Unità Operativa Complessa di Reumatologia at the Università di Pavia’s IRCCS Fondazione S. Matteo, in Pavia, Italy, who note that persistent chronic pain becomes disease itself, with associated substantial clinical, social and economic impact.

The coauthors observe that efficacy and tolerability problems are characteristic of all therapeutic strategies available for treating musculoskeletal pain — a reality that often limits effective analgesia and patients’ long term treatment compliance, with the result that chronic pain is persistently underestimated and under-treated.

Drs. Monti and Caporali report that Tapentadol, a novel, centrally acting analgesic recently commercialized for treatment of chronic pain, holds new promise for relief. Sold under the trade name NUCYNTA ER, Tapentadol is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action that is indicated for management of pain severe enough to require daily, round-the-clock, long-term opioid treatment and for which alternative treatment options have proved inadequate, as well as for neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults.

The coauthors explain that by combining two distinct mechanisms of action, opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI), Tapentadol introduces a new pharmacological class called MOR-NRI. Referencing several studies that demonstrated promising results with Tapentadol in managing both nociceptive and neuropathic pain, and a good tolerability profile. Concerning side effects in comparison with traditional opioids, they suggest that this novel analgesic represents a possible therapeutic option also in the rheumatologic field, particularly for treating osteoarthritis and low back pain.

Noting that musculoskeletal diseases represent a clinically and socio-economically relevant issue involving hundreds of millions of people around the world, Drs. Monti and Caporali observe that the burden of these conditions can be further increased when severe long-term pain is associated — pointing to prolonged triggers that result in activation of the pain matrix in the brain, and neuronal plasticity, with the result that pain perception can be elicited even in the absence of any peripheral stimulus.

The coauthors maintain that pain lasting beyond the expected healing time or over a three-month-period is defined as chronic, and at this stage, becomes a disease itself, with substantial clinical, psychological, social and economic impact.they cite rheumatic diseases as a prominent cause of chronic pain, noting study data indicating that musculoskeletal conditions affect one in four European adults, and citing the MAPPING study — a cross-sectional epidemiological study that analyzed prevalence of musculoskeletal conditions in an Italian population sample and revealed that these conditions are common in the general adult population, particularly in women and with increasing age. Overall prevalence of musculoskeletal conditions was found to be 26.7 percent, with the most frequent diagnosis being symptomatic peripheral osteoarthritis (OA) (8.95%), followed by soft tissue disorders (8.81%), low back pain (5.91%), and inflammatory rheumatic diseases (3.06%).

The investigators report that recent estimates on prevalence of rheumatic diseases indicate that nearly 27 million people in the United States are affected by clinical osteoarthritis, five million have fibromyalgia, up to three million have self-reported gout, rheumatoid arthritis affects 1.3 million adults, and spondylarthritides from 0.6 to 2.4 million adults.

Reviewing the shortcomings and inadequacies of current approaches to treating chronic pain, Drs. Monti and Caporali note that pain is almost constantly associated with musculoskeletal diseases, with a review of prevalence studies indicating that almost one-fifth of adult populations report widespread pain (fibromyalgia), one-third shoulder pain and up to one-half low back pain over a one-month period, citing a survey on different health aspects in the European Union, the Eurobarometer Report on Health, which included a question on musculoskeletal pain. As many as 32 percent of all respondents and 44 percent of those 55 years of age and over reported experiencing muscle, joint, neck or back pain in the previous week severe enough to affect their daily activities. Up to 25 percent of all respondents reported chronic restrictive musculoskeletal pain lasting more than three months at some point in their life. Risk factors for developing musculoskeletal pain included a lower educational profile and being of female gender.

A 2008 questionnaire conducted by the National Health and Wellness Survey on 53,525 adults in five European countries (United Kingdom, France, Spain, Germany and Italy) revealed that 22 percent of subjects had suffered from pain within the last month, 44 percent of whom experienced pain daily. Back pain was the most commonly cited condition causing chronic pain (71%), followed by joint pain, while oncologic pain accounted for only 1% of the patients. Pain severity correlated with the general health and mental status, with high incidence of depression (35%), anxiety (42%) and sleep difficulties (58%) compared to the general population.

Consequently, the researchers conclude that the burden of chronic musculoskeletal pain is clinically and socially relevant, often leading to functional disability and potentially to severe impairment of normal daily living activities. They note that roughly one-third of the Italian population is reported to have sought medical advice for musculoskeletal complaints during the previous year, and that OA is the most common joint disorder, accounting for more disability among the elderly than any other disease, with health related quality of life (HRQOL) in older patients with OA reported as being lower than that of the community-matched cohort, and similar to scores from patients with depression or advanced cancer.

Drs. Monti and Caporali contend that the previously mentioned evidence, and more from other studies clearly indicate that chronic pain has a substantial medical and social impact, and that optimal management of OA, for instance requires a combination of non-pharmacological and pharmacological modalities, with initial treatment focused on non-pharmacological approaches (e.g.: lifestyle, physical therapy), but that for patients whose symptoms are not controlled by these approaches, pharmacological treatment should then be considered. However, they observe that data focusing on pharmacologic prescription modalities of general practitioners and specialists fail to reflect the importance of effective treatment of chronic pain.

They cite as insight on the epidemiology of musculoskeletal disorders in Italy the revelation that at least 25 percent of 48,136,832 Italians aged over 18 years (2006 census) report musculoskeletal disorders, but nearly 40 percent of them don’t seek any medical attention and only four percent are treated by rheumatologists, and that the American Academy of Pain Medicine estimates that more than four of every 10 patients with moderate-to severe pain don’t get adequate relief from analgesics, and a quarter of patients change health care professionals more than once because of perceptions of suboptimal pain care.

They reference data from the AMICA study analyzing pharmacologic and non-pharmacologic prescription patterns of general practitioners and specialists suggesting that a consistent number of patients don’t receive any treatment at all, while the majority of them are treated with mild analgesics, NSAIDs or coxibs, and there are efforts being made to reduce use of NSAIDs to treat OA pain, particularly affecting elderly patients, in spite of the higher prevalence of musculoskeletal chronic pain in that population — probably attributable to increasing awareness of potential side effects associated with long-term use of NSAIDs, particularly affecting the gastrointestinal system. They also note a striking decrease in the use of coxibs after the withdrawal of rofecoxib from the market due to evidence of an increased risk of myocardial infarction. The American Geriatrics Society recommendations suggest acetaminophen as first choice pharmacotherapy in the elderly, with NSAIDs and COX-2 selective inhibitors to be considered rarely, with extreme caution, in highly selected individuals who should be routinely assessed for GI and renal toxicity, hypertension, heart failure. The AGS guidelines say patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life because of pain should be considered for opioid therapy.

However, Drs. Monti and Caporali note that surprisingly, despite guidelines recommendations, reduced prescription rates of anti-inflammatory drugs (NSAIDS, Coxibs) was not compensated for by increases in use of alternate analgesic medications with proved efficacy, such as acetaminophen or weak opioids, and they contend that the tendency to avoid opioid use in treating musculoskeletal pain is not justified by published evidence.

They refer to expert OARSI group consensus recommendations for management of hip and knee OA from a systematic review of existing guidelines, underlining, with high levels of evidence and consensus, that weak opioids can be considered for treatment of refractory pain when other pharmacological agents have been ineffective or are contraindicated. The researchers also note that in exceptional circumstances stronger opioids could also be prescribed — for example a recent Cochrane review reporting some evidence of efficacy and function improvement in patients treated with opioids for chronic back pain. The American Heart Association also lists opioids among medications with a more favorable safety profile, together with acetaminophen, as preferable to NSAIDs and particularly coxibs, in patients with coronary artery disease, and American Pain Society guidelines say opioids, including tramadol, represent a valid option after maximizing non-opioid pain relief strategies also in patients with back pain and may also be appropriate for patients with neuropathic pain who have not achieved adequate analgesia despite treatment with antineuropathic agents (e.g.: anticonvulsants and tricyclic antidepressants/dual reuptake inhibitors).

The researchers also note that substantial differences exist in analgesic prescription rates among different European countries, with opioids prescribed much more readily in Northern Europe compared to the South (including Italy) or the East, leading to the impression that pain treatment seems to be driven mainly by tradition and personal experience rather than by international guidelines. They deduce that phenomenon they refer to as “opiophobia” can partly be explained by the fear of adverse events induced by opioids, such as one patient in every two experiencing at least one adverse event such as nausea (21%), constipation (15%), dizziness (14%), and drowsiness or somnolence (14%), and with one in five patients discontinuing treatment because of adverse events. Opioid neurotoxicity, dizziness and sedation are also significant issues, especially among the elderly. More serious potential adverse reactions include an association between sleep-disordered breathing and chronic opiate use in a dose-dependent fashion, opiate-induced hypogonadism, and possible negative cardiovascular effects such as increased risk of myocardial infarction or heart failure, as well as increased pneumonia risk among the elderly, possibly associated with immunosuppression. Tolerance and addiction are also relevant issues when prescribing opioids, with risk factors for opioid abuse including history of previous drug conviction, mental health disorders, and past alcohol or illicit drug abuse. Moreover, opioid treatment may not be effective because of individual variations to pure-opioid agonist therapies and different degrees of central sensitization.

Against this backdrop, Drs. Monti and Caporali observe that need for new therapeutic options is urgent, and Tapentadol’s synergistic interaction of two combined analgesic effects offers particular advantages in terms of efficacy and tolerability. With Tapentadol, analgesia is obtained at different levels through modulation of the opioid system and the descending inhibitory noradrenergic systems. Tapentadol is only 2- to 3-fold less potent than morphine, indicating that the drug’s NRI component contributes to its analgesic effect in an additive and synergistic manner, and the two mechanisms of action result in different modulations of acute and chronic pain with the opioid agonism primarily effective in controlling acute pain, whereas noradrenaline reuptake inhibition is mainly effective in modulating chronic pain. They report that the efficacy of tapentadol in neuropathic pain conditions has been demonstrated in several experimental models, and in that therapeutic category Tapentadol shows even higher potency than morphine, and the inhibitory effect on disease-related hyperalgesia suggests a superior efficacy profile of Tapentadol compared with classical opioids, including morphine, in a rodent animal model of heat hyperalgesia Efficacy on neuropathic pain has also been reported in clinical studies, especially in controlling chronic back pain with radicular involvement and diabetic neuropathy, and additionally the MOR-NRI mechanism of action can provide tolerability advantages. Moreover, Tapentadol’s noradrenergic components have an opioid-sparing effect, thus reducing GI adverse effects compared to traditional opioids, and the drug has minimum effect on serotonin reuptake, thereby reducing its effects on the enteric nervous system (constipation, nausea and vomiting) and its safety profile enhanced by the fact that no relevant interactions with enzymes of the P450 cytochrome system have been registered. Binding to plasma protein is low, reducing pharmacokinetic interaction with other medications, Monti and Caporali reporting that randomized clinical trials (RCT) have consistently demonstrated the efficacy and tolerability of tapentadol prolonged release (PR) (100-250 mg bid) in management of moderate to severe chronic pain caused by OA and low back pain.

All the sub-scale scores and the global score of the Canadian WOMAC (Western Ontario and McMaster Universities osteoarthritis index), a self-administered questionnaire used to assess pain, show disability and joint stiffness in knee and hip OA, significantly improved and quality of life also improved by tapentadol treatment, with significant reduction of anxiety and depression reported by patients). The majority of adverse events (95.7%) were considered to be of mild or moderate intensity, mainly affecting the GI system. Tapentadol proved to be effective also in the management of neuropathic pain in the setting of severe chronic low back pain that was inadequately managed with WHO step I and II analgesics, and significant improvements in pain intensity and neuropathic pain symptoms have been observed on an open-label, phase 3 study analyzing the effect of Tapentadol vs strong opioids in the management of chronic low back pain. Pain relief was comparable to equianalgesic doses of strong opioids, but with improved tolerability.

Drs. Monti and Caporali conclude that pain is too often underestimated and inadequately treated — mainly due to tolerability problems connected with traditional analgesics and unjustified low prescription rates of opioids, and observe that Tapentadol has shown promising results in management of both nociceptive and neuropathic pain and good tolerability profile, particularly concerning GI side effects, compared to traditional opioids. The new drug also represents a possible therapeutic option in the rheumatologic field, particularly in treatment of pain, although they caution that further studies are needed to assess the role of tapentadol in management of pain connected with inflammatory arthritis or caused by vasculitisosteoarthritis and low back pain

Sources:
Reumatismo – the Official Journal of the Italian Society of Rheumatology (SIR)
Unità Operativa Complessa di Reumatologia at the Università di Pavia

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