Treatment of Pain and Inflammation

Aspirin and other NSAIDs are effective in treating mild-to-moderate pain of various origins, including headache, toothache, and diffuse muscular aches and soreness. Aspirin appears to be especially useful in treating pain and inflammation in musculoskeletal and joint disorders.71,87,89 The safe and effective use of aspirin in both rheumatoid arthritis and osteoarthritis is well documented (see Chapter 16).53,66,84 Aspirin is also recommended for treating the pain and cramping associated with primary dysmenorrhea.70 

SECTION 4 Drugs Used to Treat Pain and Inflammation 

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The dimethylheptyl side-chain analogue of 9-carboxy-A -THC, ajulemic acid, CT-3, (166) is currently in clinical development for treatment of pain and inflammation [121, 122]. Compound (166) does show some affinity for CBi and CB2 receptors, but may also exert anti-inflammatory and analgesic effects through other mechanisms. It does not appear to be psychoactive in humans [123]. 

The FDA approved this selective cyclooxigenase (COX)-2 inhibitor (Vioxx) for the treatment of pain and inflammation in 1999. This NSAID demonstrated to have a lower risk of side effects such as gastrointestinal ulcers and bleeding than nonse-lective COX inhibitors, for example, ibuprofen. In 2004, a long-term study of Vioxx in patients at increased risk of colon polyps was halted because of an increased cardiovascular risk (heart attack, stroke) in the rofecoxib group. Subsequently, Merck withdrew the drug from the world market at the end of September 2004 [46]. 

In addition to the treatment of pain and inflammation, COX-2 inhibitors might be of benefit in other indications. Expression of COX-2 in colon cancer, intestinal adenomas, and other cancer cells as well as clinical studies with COX-2 inhibitors, suggest the use of COX-2 inhibitors in cancer (Masferrer et al., 1999). Expression of COX-2 in angiogenesis follows the same route since angiogenesis is important for blood supply and hence the growth of many tumors. 

Clinical use Flurbiprofen is a nonsteroidal antiinflammatory drug used for the treatment of pain and inflammation associated with musculoskeletal and joint disorders as well as neuralgias, dysmenorrhoea and postoperative pain. 

Members of the akuammiline alkaloid family also hold promise for treatment of pain and inflammation. Scholarisin I (60) and scholarisin VI (65) were claimed as selective inhibitors of COX-2, while pseudoakuammigine (13) has been reported to have in vivo anti-inflammatory and analgesic activity in rats observed via the carrageenan-induced paw edema and tail flick models respectively. " Picrinine (5) has also been su ested to have antiinflammatory and analgesic activity in mice based on results from various in vivo assays, while (Z)-alstoscholarine (29) was disclosed to be an inhibitor of nuclear factor-KB. ... 

Although NSAIDs are effective in the treatment of pain and inflammation, their routine and long-term administration is limited, because of their GI and renal side effects. COX isozymes are the main targets of NSAIDs. While the inhibition of COX-2 is related to anti-inflammatory effects, that of COX-1 is associated with the adverse effects. The idea behind developing COX-2 inhibitors was to have a NSAID devoid of GI toxicity. However, GI toxicity depends on multiple factors, not just COX-2 selectivity. 

Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by intra-articular, systemic, or subcutaneous routes, depending on the degree of pain and inflammation. The most commonly used oral corticosteroid is prednisone. The recommended dose is 30-50 mg/d for 1-2 days, tapered over 7-10 days. Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications. 

The present invention is generally directed to non-psychoactive derivatives of A6-THC-7-oic acid, which have been shown to be potent analgesic and anti-inflammatory agents and to possess leukocyte antiadhesion activities. The invention is further related to the use of these derivatives as therapeutic agents in the treatment of pain and tissue inflammation, especially that associated with long-term illnesses such as rheumatoid arthritis. 

Non-steroidal anti-inflammatory agents are of prime clinical interest in the control of pain and inflammation associated with a wide variety of rheumatoid- and non-rheumatoid-related disorders. In a continuous search for well-tolerated and effective agents for the treatment of human diseases, over 100 groups of new chemical entities have been synthesized and disclosed in the literature as potential anti-inflammatory drugs. 

Since non-psychoactive cannabinoids, such as CBD and CBN, are able to induce a marked decrease in the levels of interferons, pro-inflammatory cytokines, and chemokines after stimulation with LPS [63], this activity is unlikely to be mediated by interaction with CB receptors, while the involvement of the adenosine signaling has, rather, been postulated [64], CBD and CBG have also demonstrated a non-CB-mediated inhibition of the proliferation of human keratinocytes, supporting a potential role for cannabinoids in the treatment of psoriasis [65]. A synthetic cannabinoid, ajulemic acid (31), has been proposed for treatment of arthritis and for the management of pain and inflammation in multiple sclerosis patients [66]. 

The daily oral dose of diclofenac is 50-150 mg. Diclofenac is also available as eye-drops for the treatment of non-specific inflammation of the eye and for the local therapy of eye pain. 

Erythema, inflammation, pain, and itching caused by contact dermatitis can be effectively treated with topically applied corticosteroids. With such a wide range of products and potencies available, an appropriate steroid selection is based on severity and location of the lesions. Table 62-6 shows a list of topical steroids and their potencies. Higher-potency preparations are used in areas where penetration is poor, such as on the elbows and knees. Lower-potency products should be reserved for areas of higher penetration, such as on the face, axillae, and groin. Low-potency steroids are also recommended for the treatment of infants and children.32,33... 

Alefacept (Amevive) is a dimeric fusion protein that binds to CD2 on T cells to inhibit cutaneous T-cell activation and proliferation. It also produces a dose-dependent decrease in circulating total lymphocytes. Alefacept is approved for treatment of moderate to severe plaque psoriasis and is also effective for treatment of psoriatic arthritis. Significant response is usually achieved after about 3 months of therapy. The recommended dose is 15 mg intramuscularly once weekly for 12 weeks. Adverse effects are mild and include pharyngitis, flu-like symptoms, chills, dizziness, nausea, headache, injection site pain and inflammation, and nonspecific infection. 

Phenylalanine Decreases pain and inflammation in the treatment of rheumatoid arthritis and osteoarthritis... 

The FDA approves Vioxx, an anti-inflammation drug for treatment of osteoarthritis and some other conditions that cause acute pain. 

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