Tramadol: a Wonder Drug for the Treatment of Chronic Pain?

Editorial

Tramadol: a wonder drug for the treatment of chronic pain?

“Nowadays, we should consider tramadol as a ‘silver bullet’, rather than as a ‘wonder drug’, for its extreme effectiveness in chronic pain management.”

“When the only tool you have is a hammer … linked COX-2 inhibitors with serious cardio it is tempting to treat everything as if it were vascular and/or cardiorenal effects and/or seri- a nail.” ous cutaneous adverse reactions, particularly – Abraham Maslow, 1962. The Psychology of at anti-inflammatory doses or when used long Consalvo Mattia Science: A Reconnaissance term. Regulatory authorities in both Europe and Author for correspondence: the USA have responded to these data with the Department of Anaesthesia, Chronic pain is one of the most prevalent, withdrawal of rofecoxib and valdecoxib, and Intensive Care Medicine & Pain costly and disabling conditions in both clinical the strengthening of prescribing advice on all Therapy, Sapienza University practice and the workplace, yet often remains anti-inflammatory drugs [5]. of Rome, ICOT Polo Pontino, inadequately treated. Musculoskeletal condi- Scientific societies, including the American Rome, Italy tions, such as low-back pain and osteoarthri- College of Rheumatology (ACR) [6], American Tel.: +39 335 333 668 tis (OA), are the leading causes of disability Pain Society (APS) [7] and European League [email protected] among individuals of working age. The goals of Against Rheumatism (EULAR) [8], have pub- adequate pain management include pain relief, lished treatment guidelines to assist clinicians minimizing disability, improving quality of life to achieve effective chronic pain management. and preventing progression of the disease [1]. Safety is a core concern in all these guidelines, Optimal management requires a combination especially for chronic conditions such as low- of nonpharmacological and pharmacological back pain and OA that require long-term treat- modalities of therapy [2]. ment. There is a consensus among recommendations that paracetamol should be the first-line “The goals of adequate pain management analgesic agent due to its favorable side effect include pain relief, minimizing disability, and safety profile. Owing to the selective inhibi- Flaminia Coluzzi improving quality of life and preventing tion of COX in the CNS, paracetamol does not Sapienza University of Rome, progression of the disease.” impair GI, renal and platelet function [9]. Rome, Italy When the anti-inflammatory component is NSAIDs have been widely used in the man- required, the OA Research Society International agement of chronic pain. However, patients (OARSI) guidelines recommend NSAIDs, receiving long-term NSAID therapy may expe- including COX-2 inhibitors, for the treatment of rience severe gastrointestinal (GI) symptoms. symptomatic OA of the hip or knee at minimal NSAID-related ulceration and bleeding is esti- effective doses only; whereas long-term NSAID mated to result in up to 20,000 deaths each year use should be avoided if possible [10]. in the USA [3]. Attempts to reduce the serious GI All the recent pain management guide- adverse effects of the NSAIDs by the introduc- lines have shifted their emphasis from the use tion of the highly selective COX-2 inhibitors of NSAIDs and COX-2 inhibitors to opioids. have only had limited benefit in reducing these Therefore, when greater analgesia is desired, the untoward actions. COX-2-specific inhibitors, addition of weak opioids is recommended, based such as celecoxib, may spare gastric mucosal on a preferable GI and cardiovascular profile, prostaglandin synthesis and, consequently, compared with the prolonged use of high doses cause less GI injury. However, both COX-2- of NSAIDs [11]. specific inhibitors and NSAIDs may affect Conversely, opioids are still underused, regard- fluid and electrolyte balance in some patients, less of their established analgesic efficacy. The resulting in fluid retention, edema and hyper- fear of adverse effects and the need of risk assess- tension [4]. Moreover, accumulating data have ment for scheduled opioids remain problematic

for many healthcare providers. Pain management on respiration. While m‑opioid agonists have guidelines recommend that strong opioids only undesirable effects on GI function, resulting in be used for the management of severe pain in OA nausea, emesis and especially constipation, these in exceptional circumstances, when more conser- effects are less severe with tramadol and attenu- vative methods have failed [12]. The use of opi- ate over time. Tramadol has only a minor delay- oids requires close supervision, especially in the ing effect on colonic transit, and no effect on elderly with cognitive decline, since drug actions upper GI transit or gut smooth muscle tone [18]. on the CNS and peripheral nervous systems can Despite its favorable profile, it is a conceptual result in significant adverse effects of these agents mistake to consider tramadol a ‘panacea’, a sup- (e.g., constipation, drowsiness, respiratory and posed remedy that would cure all types of pain. cardiovascular decline) [13]. The research of the so-called ‘wonder drugs’ failed to give positive results in several medical “Tramadol ... is recommended as an fields. In particular, owing to the complexity of alternative to NSAIDs and strong opioids in pain mechanisms, it is unreliable to think that various treatment guidelines.” the rule ‘one fits all’ could be applicable to any analgesic drug. The beneficial effects of ‘nontramadol opioids’, Although we often think of pain as a homo- as defined in the last Cochrane systematic review geneous sensory entity, several distinct types on oral or transdermal opioids for OA of the exist. Current analgesic treatment is aimed at knee or hip, are outweighed by large increases in suppressing or controlling symptoms; however, the risk of adverse events. Therefore, they should a better approach should be a mechanism-based not be routinely used, even if osteoarthritic pain pain management, which includes a disease- is severe [14]. modifying treatment strategy to complement In light of this consideration, the use of tra- the existing approach of symptom control [19]. madol becomes readily apparent. Tramadol, The identification of the multiple mechanisms as an atypical opioid with a low potential for responsible for the production of distinct pain drug tolerance and abuse, is well suited for the syndromes and their molecular components has management of refractory pain and, as such, is been a major advance in our understanding of recommended as an alternative to NSAIDs and pain and represent the first step for the develop- strong opioids in various treatment guidelines. ment of pharmacologic tools that act specifically Tramadol has been demonstrated to be effec- on these mechanisms. tive in the treatment of a wide range of acute and Nowadays, we should consider tramadol as a chronic pain syndromes, including neuropathic ‘silver bullet’, rather than as a ‘wonder drug’, for its pain, and it is generally well tolerated. The APS extreme effectiveness in chronic pain management. recommends tramadol, alone or in combination with acetaminophen or NSAIDs, for the man- “Unlike NSAIDs, tramadol does not agement of OA pain when NSAIDs alone pro- irritate the gastrointestinal mucosa, or duce inadequate pain relief [15]. Unlike NSAIDs, exacerbate hypertension or congestive heart tramadol does not irritate the GI mucosa, or failure, making it potentially useful for exacerbate hypertension or congestive heart fail- the elderly.” ure, making it potentially useful for the elderly. For patients awaiting total joint replacement sur- Tramadol is a centrally acting analgesic with gery, tramadol may be a good analgesic option two mechanisms of action in a single molecule. if NSAIDs or COX-2-specific inhibitors are not Tramadol acts both on the opioidergic system, tolerated or provide suboptimal pain relief. with an affinity for m‑opioid receptor approxi- The most recent recommendations of the mately 6000-fold less than that of morphine, American Heart Association include trama- and on the descending monoaminergic inhibi- dol, not NSAIDs or COX-2-specific inhibitory system that physiologically modulates pain tors, as first-line therapy for musculoskeletal perception. Tramadol hydrochloride exists as a symptoms in patients with cardiovascular dis- racemic mixture with the (+)-enantiomer and ease or risk factors [16]. The fixed association the (-)-enantiomer, and at least some of their tramadol/paracetamol is a safe and easy solution metabolites, having different effects. (+)-trama- for mild-to-moderate chronic pain [17]. dol and (+)-O-desmethyl-tramadol (M1), the Compared with other centrally acting anal- main analgesic effective metabolite, are agonists gesics, tramadol has no clinically relevant of the m‑opioid receptor. (+)-tramadol inhibits cardiovascular effects and insignificant effects serotonin reuptake and (-)-tramadol inhibits

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norepinephrine reuptake, enhancing inhibitory Conversely to tramadol, tapentadol is not depen- effects on pain transmission in the spinal cord. dent on metabolic activation; therefore, its anal- The O-demethylation of tramadol to the active gesic efficacy is not affected by the activity of any metabolite M1 is catalyzed by the liver enzyme cytochrome. It exhibited analgesic effects across cytochrome P450 2D6. Therefore, the observed multiple pain models, with a significantly lower variability in the pharmacokinetic properties of incidence of GI-related adverse events compared tramadol can partly be ascribed to cytochrome with equivalent doses of oxycodone in patients P450 polymorphism [18]. with low-back pain and OA [21]. Tapentadol This dual mechanism of action by which anal- could therefore represent a ‘realistic alternative’ gesia may be achieved with tramadol includes, in to strong opioids for severe pain. a ‘single drug’, the concept of multimodal anal- Chronic pain is still far from being a solved gesia, which involves the use of different classes problem. The search for a ‘magic wand’ does of analgesics and/or different sites of administra- not represent the right solution. Rather, we tion to provide synergistic analgesic effects and should focus on drugs with an appropriate bal- minimize adverse drug effects. ance between analgesic efficacy and tolerabil- These different, complementary mechanisms ity in order to improve patient adherence to of action could be of particular relevance in some long-term treatments. types of pain that are generally considered to be relatively unresponsive to opiates, such as Financial & competing interests disclosure neuropathic pain syndromes. The authors have no relevant affiliations or financial A novel, centrally acting analgesic with two involvement with any organization or entity with a finan- mechanisms of action, termed tapentadol, is cur- cial interest in or financial conflict with the subject matter rently under evaluation. Its analgesic activity is or materials discussed in the manuscript. This includes achieved through micro-opioid receptor ago- employment, consultancies, honoraria, stock ownership or nism and noradrenaline reuptake inhibition in options, expert testimony, grants or patents received or the CNS. Tapentadol represent a new alternative pending, or royalties. drug for moderate-to-severe pain, to be located No writing assistance was utilized in the production of in the ‘third step’ of the analgesic ladder [20]. this manuscript.

Bibliography 6 American College of Rheumatology: 10 Zhang W, Moskowitz RW, Nuki G Recommendations for the medical et al.: OARSI recommendations 1 Coluzzi F, Mattia C: Chronic non-cancer management of osteoarthritis of the hip and for the management of hip and knee pain: focus on once-daily tramadol knee: 2000 update. American College of osteoarthritis, Part II: OARSI formulations. Ther. Clin. Risk Manag. 3, Rheumatology Subcommittee on evidence-based, expert consensus guidelines. 819–829 (2007). Osteoarthritis Guidelines. Arthritis Rheum. Osteoarthr. Cartil. 16, 137–162 2 Chou R, Huffman LH; American Pain 43, 1905–1915 (2000). (2008). Society; American College of Physicians: 7 Chou R, Qaseem A, Snow V et al.; Clinical 11 Airakinsen O, Brox JI, Cedraschi C Medications for acute and chronic low back Efficacy Assessment Subcommittee of the et al.: European guidelines for the pain: a review of the evidence for an American College of Physicians; American management of chronic non-specific American Pain Society/American College College of Physicians; American Pain Society low back pain. Eur. Spine J. 15, S192–S300 of Physicians Clinical Practice Guideline. Low Back Pain Guidelines Panel: Diagnosis (2006). Ann. Intern. Med. 147, 505–514 and treatment of low back pain: a joint 12 Goodwin JL, Kraemer JJ, Bajwa ZH: (2007). clinical practice guideline from the American The use of opioids in the treatment of 3 Ofman JJ, MacLean CH, Straus WL et al.: College of Physicians and the American Pain osteoarthritis: when, why, and how? A meta-analysis of severe upper Society. Ann. Intern. Med. 147, 478–491 Curr. Rheumatol. Rep. 11, 5–14 gastrointestinal complications of nonsteroidal (2007). (2009). antiinflammatory drugs.J. Rheumatol. 29, 8 Zhang W, Doherty M, Harden N et al.: 13 American Geriatrics Society Panel on 804–812 (2002). EULAR evidence based recommendations Persistent Pain in Older Person: The 4 Farkouh ME, Greenberg BP: An for the management of hip osteoarthritis: management of persistent pain in older evidence-based review of the cardiovascular report of a task force of the EULAR persons. J. Am. Geriatr. Soc. 50, S205–S24 risks of nonsteroidal anti-inflammatory Standing Committee for International (2002). drugs. Clinical Studies Including Therapeutics 14 Nuesch E, Rutjes AW, Husni E et al.: Am. J. Cardiol. 103, 1227–1237 (2009). (ESCISIT). Ann. Rheum. Dis. 64, 669–681 Oral or transdermal opioids for (2005). 5 Jaksch W, Dejaco C, Schirmer M: 4 years osteoarthritis of the knee or hip. Cochrane after withdrawal of rofecoxib: where do we 9 Mattia C, Coluzzi F: What anaesthesiologists Database Syst. Rev. 4, CD003115 stand today? Rheumatol. Int. 28, 1187–1195 should know about paracetamol. Minerva (2009). (2008). Anestesiol. 75, 644–653 (2009).

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15 Chou R, Fanciullo G, Fine P et al.: American 17 Mattia C, Coluzzi F, Sarzi Puttini P et al.: 20 Tzschentke TM, Jahnel U, Kogel B et al.: Pain Society-American Academy of Pain Paracetamol/tramadol association: the easy Tapentadol hydrochloride: a next-generation, Medicine Opioids Guidelines Panel: Clinical solution for mild–moderate pain. Minerva centrally acting analgesic with two guidelines for the use of chronic opioid Med. 99, 369–390 (2008). mechanisms of action in a single molecule. therapy in chronic noncancer pain. J. Pain 10, 18 Grond S, Sablotzki A: Clinical pharmacology Drugs Today (Barc.) 45, 483–496 113–130 (2009). of tramadol. Clin. Pharmacokinet. 43, (2009). 16 Antman EM, Bennett JS, Daugherty A et al.: 879–923 (2004). 21 Hale M, Upmalis D, Okamoto A et al.: Use of nonsteroidal antiinflammatory drugs. 19 Woolf CJ; American College of Physicians; Tolerability of tapentadol immediate release An update for clinicians. A scientific American Physiological Society: Pain: moving in patients with lower back pain or statement from the American Heart from symptom control toward mechanism- osteoarthritis of the hip or knee over 90 days: Association. Circulation 115, 1634–1642 specific pharmacologic management.Ann. a randomized, double-blind study. Curr. Med. (2007). Intern. Med. 140, 441–451 (2004). Res. Opin. 25, 1095–1104 (2009).

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