Topical NSAIDs

NSAIDs reversibly inhibit the enzyme cyclooxygenase (prostaglandin endoperoxide synthase or COX), now recognised to consist of two isoforms, COX‐1 and COX‐2, mediating production of prostaglandins and thromboxane A2 (Fitzgerald 2001). However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cox‐dependent prostanoid formation (Hawkey 1999). Systemically, prostaglandins mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive (pain) processes. The rationale behind topical application is based on the ability of NSAIDs to inhibit cox enzymes locally and peripherally, with minimum systemic uptake. Their use is therefore limited to conditions where the pain is fairly superficial, such as joints and skeletal muscle, rather than visceral pain.

Once the drug has reached the site of action, it must be present at a sufficiently high concentration to inhibit cox enzymes and produce pain relief. It is probable that topical NSAIDs exert their action both by local reduction of symptoms arising from periarticular and intracapsular structures. Tissue levels of NSAIDs applied topically certainly reach levels high enough to inhibit COX‐2. Plasma concentrations found after topical administration, however, are only a fraction (usually much less than 5%) of the levels found in plasma following oral administration. Topical application can potentially limit systemic adverse events by minimizing systemic concentrations of the drug. We know that upper gastrointestinal bleeding is low with chronic use of topical NSAIDs (Evans 1995), but have no certain knowledge of effects on heart failure, or renal failure, both of which are associated with oral NSAID use.

Topical rubefacients

Rubefacients cause irritation of the skin, and are believed to relieve pain in muscles, joints and tendons, and other musculoskeletal pains in the extremities by counter‐irritation (BNF 2009). The term "counter‐irritant" derives from the fact that these agents cause a reddening of the skin by causing the blood vessels of the skin to dilate, which gives a soothing feeling of warmth. The term counter‐irritant refers to the idea that irritation of the sensory nerve endings alters or offsets pain in the underlying muscle or joints that are served by the same nerves (Morton 2002). There has been confusion about which compounds should be classified as rubefacients. Some compounds, such as salicylates, are related pharmacologically to aspirin and NSAIDs, but for the form that they are often used in for topical products (often as amine derivatives) their principal action is to act as skin irritants. We will include salicylates and nicotinate esters as rubefacients.

Topical capsaicin

Capsaicin is the active compound present in chili peppers, responsible for making them hot when eaten. It binds to nociceptors (sensory receptors responsible for sending signals that cause the perception of pain) in the skin, releasing pro inflammatory neuropeptides, such as substance P, which cause neurogenic inflammation. There is an initial excitation of the neurons and a period of enhanced sensitivity to noxious stimuli, usually perceived as itching, pricking or burning sensations. Enhanced sensitivity is followed by a refractory (unresponsive) period with reduced sensitivity and, after repeated applications, persistent desensitisation. The mechanisms of desensitisation remain unclear. It is thought that degenerative changes in the primary sensory neuron result in loss of peripheral or central nociceptor‐specific macromolecules and receptors, and that these degenerative changes can affect distant parts of the primary sensory neuron (Jancso 2008). The resulting reduction of sensation is associated with degeneration of epidermal nerve fibres, which is at least partially reversible (Nagy 2004; Nolano 1999; Simone 1998). It is the theoretical ability of capsaicin to desensitise nociceptors that is exploited for therapeutic pain relief (Holzer 2008).

Topical lidocaine

Topical lidocaine dampens peripheral nociceptor sensitisation and central nervous system hyperexcitability. It may benefit patients with postherpetic neuralgia or traumatic nerve injury, where its lack of systemic side effects makes it an attractive option. Lidocaine is an amide‐type local anaesthetic agent that acts by stabilising neuronal membranes. It impairs membrane permeability to sodium, which in turn blocks impulse propagation, and thus dampens both peripheral nociceptor sensitisation, and eventually central nervous system hyperexcitability. It also suppresses neuronal discharge in A delta and C fibres. Regenerating nerve fibres have an accumulation of sodium channels. When lidocaine binds to such sodium channels it initiates an 'inactive state' from which normal activation is unable to occur. Lidocaine reduces the frequency rather than the duration of sodium channel opening. In a small dose it inhibits ectopic discharges, although it does not disrupt normal neuronal function. Lidocaine also suppresses spontaneous impulse generation from dorsal root ganglia, where the postherpetic neuralgia virus remains dormant after initial infection by varicella zoster (chickenpox) (Khaliq 2007).

Topical opioids

Topically applied opioids bind to peripheral opioid receptors on the terminals of nociceptive nerves in damaged and inflamed tissue, with analgesic effects through reduced pain perception and reaction to pain (Stein 2003).