Pain subsides là gì

Managing pain from chronic conditions, such as, but not limited to, osteoarthritis and rheumatoid arthritis, requires the clinician to balance the need for effective analgesia against safety risks associated with analgesic agents. Osteoarthritis and rheumatoid arthritis pain is incompletely understood but involves both nociceptive and non-nociceptive mechanisms, including neuropathic mechanisms. Prevailing guidelines for arthritis-related pain do not differentiate between nociceptive and non-nociceptive pain, sometimes leading to recommendations that do not fully address the nature of pain. NSAIDs are effective in treating the nociceptive arthritis-related pain. However, safety concerns of NSAIDs may cause clinicians to undertreat arthritis-related pain. In this context, combination therapy may be more appropriate to manage the different pain mechanisms involved. A panel convened in November 2010 found that among the currently recommended analgesic products for arthritis-related pain, fixed-low-dose combination products hold promise for pain control because such products allow lower doses of individual agents resulting in decreased toxicity and acceptable efficacy due to synergy between the individual drugs. Better evidence and recommendations are required to improve treatment of chronic arthritis-related pain.

Nonsteroidal Anti-Inflammatory Drugs [NSAIDs]

Both selective and nonselective cyclooxygenase [COX] inhibitors have antipyretic, anti-inflammatory and analgesic effects and are widely used in treating many painful conditions, including rheumatic diseases [30]. NSAIDs are effective and widely available in over-the-counter formulations and in prescription products. Examples include ibuprofen, naproxen, diclofenac, and celecoxib. NSAIDs are frequently used without considering the relative contraindications since most NSAIDs are sold over the counter [31]. Conventional NSAIDs are associated with gastrointestinal [GI] side effects [32]. Estimates of the number of deaths from NSAID-related gastrointestinal bleeding vary widely and figures of approx. 3500 to 16.500 per year are quoted for the US in a recent FDA report [33]. Both conventional NSAIDs and COX-2 inhibitors are associated with increased cardiovascular risk [34-37]. NSAIDs may increase blood pressure [38], particularly in hypertensive patients [39]. Of all NSAIDs, naproxen seems to pose the least cardiovascular risk [37, 40], although naproxen is associated with the same risk for myocardial infarction as other NSAIDs [35].

Contrary to some clinical assumptions, gastrointestinal risk is present at first dose with a non-selective NSAID, and co-therapy with a proton pump inhibitor [PPI] does not guarantee complete protection [41]. COX-2 selective NSAIDs, especially in combination with a PPI, provide prophylaxis against NSAID gastropathy [42]. The incidence and severity of gastrointestinal adverse events associated with NSAID therapy increases with advancing age, limiting their clinical utility in the geriatric population, particularly in concomitant use with low-dose aspirin, taken by many elderly patients for cardioprotection [43, 44]. NSAIDs should be used at the lowest effective dose for the shortest possible period of time in chronic pain populations. In addition to the above mentioned risks, NSAIDS may interact with many other medicinal products [45-48] and special caution and close monitoring is recommended in particular for elderly patients and patients with a history or symptoms indicative of gastrointestinal disorders, patients with renal, cardiac or hepatic impairment, a history of hypertension, asthma, seasonal allergic rhinitis, systemic lupus erythematosus [SLE] and mixed connective tissue disorders [45-48]. Very rarely serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with the use of NSAIDs [45-48]. Accumulated toxicity and the above-mentioned potential risks are the main reasons that there are no suitable agents for long-term treatment [49, 50].

Paracetamol

The antipyretic and analgesic effects of paracetamol [acetaminophen or APAP] have been known since the late 19th century. It is often considered a first-line approach to pain management [51], although there is a risk of hepatoxicity at high doses. Even at recommended therapeutic doses of paracetamol up to 4 g/d, otherwise healthy adults can exhibit abnormally high levels of aminotransferase [52]. Although high doses of paracetamol are known to be toxic, such supratherapeutic doses of paracetamol are sometimes prescribed and dispensed [53]. Paracetamol is widely available over the counter and in prescription products and many combination products contain paracetamol, but patients may equate the drugs familiarity with safety and wrongly consider it more or less harmless. Twelve percent of patients believe that it is not possible to ingest a toxic dose of paracetamol [54]. Furthermore, even patients who understand the potential toxicity of paracetamol may be unaware that it is found in a wide range of over-the-counter products from cold medicines to headache remedies. Patients taking such over-the-counter products may be unaware of hidden paracetamol in such products and unaware of the risk of high cumulative doses [54].

Paracetamol was shown in one study to significantly increase blood pressure in ambulatory patients with coronary artery disease [55]. The frequency of use of paracetamol has been independently associated with a moderately increased risk of hypertension in men [56]. There is some evidence in the literature to suggest that paracetamol may have an anti-inflammatory effect in patients with OA of the knee [57]. Although earlier reports describe paracetamol as having no or minimal anti-inflammatory effects, increasing reports suggest, that in addition, it may have a beneficial effect on inflammation distinct from the anti-inflammatory effects of NSAIDs [58]. Further study in that field is warranted.

Tramadol

Tramadol is considered a weak opioid on the WHO pain ladder [59]. Due to its differences to other opioids, it will be discussed separately here. Tramadols analgesic effect derives from a combination of an agonist action at mu-opioid receptors [low affinity of parent drug, much higher affinity of its M1, O-desmethyl, metabolite] and inhibition of neuronal reuptake of serotonin [5-HT, 5-hydroxytryptamine] and norepinephrine [60]. Tramadol has been shown to decrease pain intensity in OA patients and to improve function; active-controlled studies show that tramadol provides analgesic benefits similar to diclofenac and superior to paracetamol [61]. Extended-release formulations of tramadol have been shown effective in treating chronic pain associated with OA as well as offering improvement in pain-related sleep disorders [62].

Tramadol may be associated with a risk of dependence or abuse; the prevalence of abuse/dependence over a 12-month period in patients with chronic non-cancer pain was, however, equivalent for tramadol and NSAIDs, and significantly less than for hydrocodone [63]. In patients prone to convulsive disorders, the risk of convulsions may increase if tramadol is taken concomitantly with medication that lowers the seizure threshold. Some cases of serotonergic syndrome have been reported with the therapeutic use of tramadol in combination with other serotonergic agents such as selective serotonin re-uptake inhibitors [SSRIs] [64]. Recommended dosing should not exceed 400 mg/d, and should be reduced or closely supervised in geriatric patients [ 75 years] and those with cirrhosis or renal dysfunction [30]. Tramadol has no known anti-inflammatory effects.

Opioids

Since 1990, opioids have been recommended in the setting of long-term non-cancer pain syndromes [65]. Growing public health concerns about prescription opioid abuse and particularly about the diversion of prescribed products to the street have focused greater scrutiny on opioid prescribing practices [66-68]. Another concern regarding opioids is the perceived high danger of addiction. Various studies have, however, demonstrated that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence [69]. Concern about opioid diversion and misuse has led to the development of so-called abuse-deterrent formulations, as a means for supporting opioid access while limiting abuse and its consequences [70, 71].

Opioids are effective in treating chronic pain [72] but are associated with side effects, including nausea, constipation, and somnolence. Opioids may be appropriate for use in the elderly under close supervision, sometimes at reduced doses [24], or as low-dose transdermal treatment, e.g., buprenorphine [73, 74]. Recently, tapentadol extended-release has shown promise in the treatment of moderate to severe chronic pain related to OA [75, 76].

In summary, clinicians may be cautious in prescribing opioids to treat OA or RA for clinical, legal, or public health reasons [77].

Tricyclic Antidepressants

Amongst other mechanisms, tricyclic antidepressants [TCAs, e.g. amitriptyline, dothiepin, and imipramine] inhibit serotonin and norepinephrine reuptake and neuronal sodium channels [78]. Various tricyclic TCAs differ with regard to their antinociceptive effects, and the non-serotoninergic properties of TCAs are believed to substantially contribute to these differences [79].

TCAs provide significant pain relief in RA patients versus placebo [80-83]. The use of TCAs in arthritis has found such a wide distribution that it has been proposed that these agents along with anticonvulsants should be described as pain-modifying drugs [29]. TCAs offer arthritis patients an analgesic benefit apart from their antidepressive effects. It has been speculated that at least part of this benefit relates to improvement of fatigue and sleep disorders [84]. TCAs are associated with certain adverse events, which include sedation, dizziness, blurred vision, constipation, and dry mouth, which can be treatment limiting. Dry mouth can be of particular concern for RA patients with secondary Sjögrens syndrome [20]. Cardiac toxicity is a concern with TCAs, and the NeuPSIG guidelines [Neuropathic Pain Special Interest Group] recommend prescribing TCAs with caution in patients with ischemic cardiac disease or ventricular conduction abnormalities [85]. Some TCAs, e.g. amitriptyline, are listed on the recently revised Beers list [American Geriatrics Society] of potentially inappropriate medication use in older adults with a strong recommendation to avoid using them because they are highly anticholinergic, sedating, and cause orthostatic hypotension [86]. Since arthritis primarily occurs in the elderly, TCAs are usually not suitable.

Anticonvulsants

Anticonvulsants, e.g., gabapentin and pregabalin, bind to the alpha2delta subunit of calcium channels and modulate the release of neurotransmitters, including glutamate, noradrenalin, serotonin, and substance P. As such, these agents may provide analgesic relief for patients with central sensitization. However, the mechanisms of action of these drugs are still poorly understood [87]. While known to be effective analgesics for fibromyalgia, these agents have not been studied in RA and OA populations. Pregabalin was shown in a preclinical study to be effective in reducing pain in an OA model [88]. Both agents are associated with adverse events. In a meta-analysis of pregabalin in adult acute and chronic pain patients, 18% to 28% of participants discontinued the study owing to adverse effects [n=19 studies with 7,003 patients] [89].

Serotonin Norepinephrine Reuptake Inhibitors

Serotonin norepinephrine reuptake inhibitors [SNRIs], inhibit serotonin and/or norepinephrine reuptake selectively, e.g., duloxetine and milnacipran. Overall, SNRIs are better tolerated than TCAs but may be less effective analgesics; they are not recommended as first-line drugs for analgesia in RA patients, although they may be useful to manage sleep-related symptoms [84]. A recent study found duloxetine was an effective analgesic in patients with OA of the knee [90].

Corticosteroids

Due to their potent anti-inflammatory effects, corticosteroids have been shown to be effective adjuvant analgesics in a variety of painful rheumatic conditions, including RA and other autoimmune disorders [91]. Concerns about especially long-term toxicity [92], and adverse events may reduce the clinical utility of these agents for long-term care [23]. According to the NICE guidelines for RA, patients with established RA should only continue long-term treatment with glucocorticoids when the long-term complications of glucocorticoid therapy have been fully discussed, and all other treatment options [including biological drugs] have been offered [49]. Long-term complications of glucocorticoid therapy include glucocorticoid-induced osteoporosis and risk of fracture [93], immunosuppression [94], elevated risk of infections, weight gain, thinning skin, muscle weakness, Cushings syndrome, onset of diabetes or worsening of existing diabetes, hypertension, glaucoma, cataracts, and delayed wound healing [95].

Topical Agents

Topical products, such as lidocaine, diclofenac, capsaicin, and salicylate, allow the patient to obtain localized pain relief. They are mainly used in combination with systemic agents in the treatment of pain associated with rheumatic disease. Topical agents may be analgesic sparing in combination regimens [96]. Side effects include skin irritations, which are typically mild. Topical diclofenac has been reported to be effective in relieving pain caused by OA of the knee [97-99]. Topical 1% diclofenac sodium gel was shown to be an effective analgesic in a study of 385 primary hand OA patients, with about 9% of diclofenac patients experiencing adverse events [compared to 4% in placebo group] and 5% of diclofenac patients discontinuing therapy because of adverse events [2% in placebo group] [100]. In another study of 216 patients with OA of the knee treated with topical diclofenac to manage flares, diclofenac was effective in reducing pain but caused skin irritation in 39% of patients, with 5% choosing to discontinue therapy [101]. Topical NSAIDs do not appear to have gastrointestinal adverse effects typical of oral NSAIDs [102], but long-term studies are warranted to confirm this. OA treatment with topical lidocaine [5% lidocaine medicated plaster] as monotherapy or add-on therapy resulted in significant improvements in pain intensity [103-105], physical function, and stiffness [103]. The use of topical capsaicin in OA is discussed controversially: topical capsaicin is recommended for hand OA but not for knee OA according to the ACR guidelines [American College of Rheumatology] [106], whereas according to a recent review concerns exist that capsaicin-induced nerve desensitization is not fully reversible and that its autonomic nerve effects may increase the risk of skin ulcers in diabetic patients [107].

The meeting was supported by Grünenthal GmbH, Aachen, Germany. The authors were compensated for their participation in the initial consensus meeting but did not receive honoraria for the finally agreed consensus statement and their work on the manuscript. The authors acknowledge editorial assistance from Jo Ann LeQuang [LeQ Medical, Texas, USA], Elke Grosselindemann [Brett Medical Writing, Bibra Lake, Australia] and Birgit Brett [Brett Medical Writing, Pulheim, Germany]. All costs associated with the publication of the manuscript were met by Grünenthal GmbH, Aachen, Germany.

Fixed-Dose Combination Therapies for Osteoarthritis and Rheumatoid Arthritis Pain. Only Combinations of Paracetamol with Other Analgesic Agents were Included. The List of Studies was Obtained Through PubMed Searches and Reference Lists of Pain Review Articles