Scenario

In the Casebook Pharmacy the counter assistant has referred a young man to pharmacist Eve. She asks how she can help. He says, “I've pulled a muscle in my thigh playing football. The coach - he's a physiotherapist so he should know - says it's nothing serious and it'll clear up in a couple of weeks at most, and I should just get something to rub in or put on it to ease the pain.  I've been looking on your shelves, but there are so many things there I've got no idea which to choose. Can you advise me?”

Questions

What are the main types of topical analgesics?
 
What do these products contain and how do they work?
 
What cautions apply to their use ?
 
How effective are topical analgesics?
 

Answers

The main types of topical analgesics are: NSAID preparations, rubefacients, cooling therapy preparations and heat pads.
 
 
NSAIDs
NSAIDs available in OTC topical analgesics are benzydamine, diclofenac, felbinac, ibuprofen, and salicylic acid. They exert their therapeutic action by blocking the enzyme cyclo-oxygenase, so preventing the formation of prostaglandins from arachidonic acid, which are produced when tissue is damaged and are major contributors to inflammation and pain. Topical NSAIDs are recommended on the premise that the drug acts directly at the affected site, avoiding the systemic adverse effects and side-effects that can result from oral administration. This depends on the drug being absorbed sufficiently into local tissue to exert an effect but without entering the systemic circulation. The skin presents a barrier to absorption and only a small proportion penetrates (4–25% in tests conducted on ibuprofen, depending on the formulation).1 Once absorbed, NSAIDs show a strong affinity for tissues, although there is evidence that they may be absorbed systemically first and then into the target tissue.

RUBEFACIENTS

Rubefacients are compounds that produce local vasodilation and create a sensation of warmth, exerting an analgesic effect by masking the perception of pain. Massaging greatly enhances this effect by increasing the penetration of the rubefacient into the skin and by stimulating nerve fibres that feed back messages to the brain, overriding painful stimuli. The pressure exerted also helps to disperse local tissue pain mediators. Massaging is therefore an important component of the action of topical analgesics, including NSAIDs.

Most proprietary rubefacient preparations are mixtures of several ingredients, including salicylates, nicotinates and counterirritant substances from natural sources.

Methyl salicylate, diethylamine salicylate and glycol salicylate are ingredients of many topical analgesic products. As well as being counterirritants, they are hydrolysed in the skin to salicylic acid and have an anti-inflammatory action. Nicotinates are other popular components of topical analgesics, producing vasodilatation and raised skin temperature. Other rubefacient ingredients of analgesic preparations include turpentine oil, camphor and menthol; the last produces a sensation of coolness rather than warmth. Capsicum oleoresin and capsaicin, which is obtained from it, produce a burning sensation on the skin, which is not accompanied by vasodilatation. Capsaicin works directly on nerve endings, depleting them of substance P, a pain-inducing peptide. 

COOLING THERAPY PREPARATIONS

Freeze sprays contain pressurised liquified gases such as butane that evaporate at low temperature when sprayed onto the skin, producing a loss of sensation until the nerve endings warm up again. Menthol is also included in the formulation. Freeze sprays are most useful for treating the sharp, but short-lived, pain caused by minor knocks and sports injuries. There are also cooling gel and patch preparations containing menthol. 

 
HEAT PADS
Some heat pads act as counter-irritants and contain similar rubefacient ingredients to those in creams, sprays, etc.  Others contain a supersaturated solution of sodium acetate, which acts as reusable heat reservoir. Sodium acetate crystallizes from solution at 540C, but a supersaturated solution exists at room temperature in a supercooled state.  Crystallization of the solution is triggered by pressing on a small flat disc of notched ferrous metal embedded in the liquid, causing it to flex and release microscopic adhered crystals of sodium acetate, which act as nucleation sites for recrystallization of the remainder of the solution. The process generates heat and raises the temperature to 540C. When the crystallized solution cools it remains solid but the pad can be reused by placing it in boiling water for 10-15 minutes to redissolve the sodium acetate and recreate a supersaturated solution. Once it has been returned to room temperature it can be triggered again. Another type of reusable heat pad contains material with a high specific heat capacity that cools slowly. It is heated in an oven or microwave before use. Aromatic compounds are added, in the form of ground spices or essential oils.
 
 

CAUTIONS

All topical analgesic products should be kept well away from the eyes, mouth and mucous membranes, and should not be applied to broken skin. The hands should always be washed after use. Topical analgesics should not be used on young children, whose skin is more sensitive than adults’ and in whom reactions are therefore more likely. Salicylate-containing preparations should not be used by patients sensitive to aspirin.

Topical NSAIDs are generally well tolerated; occasional local reactions have been reported, but these resolve on withdrawal of treatment. They should not be used with occlusive dressings. The systemic side-effects associated with oral NSAIDs can occur with topical agents, and the risk is increased with application of large amounts. Topical NSAIDs (except benzydamine) are contraindicated in patients who are sensitive to aspirin and other NSAIDs. They are not recommended for use by pregnant or breastfeeding women, or for children under 14 years of age. Serum levels of NSAIDs after topical administration are low, and clinically significant drug interactions are unlikely.

EFFICACY

Systematic reviews2,3,4 have found topical NSAIDs to be effective over short periods (up to 2 weeks) for chronic muscular conditions and osteoarthritis, and they would therefore appear to be suitable for the kind of acute conditions for which they are licensed for non- prescription sale. In limited studies,topical NSAIDs were found to be as effective as oral NSAIDs for sprains and strains, with a very low incidence of adverse effects.5 A  study found topical ibuprofen to be as effective as oral preparations in treating knee pain over one year in patients aged over 50.6

A systematic review of rubefacients containing salicylate and nicotinate esters concluded, from the best assessment of limited information, that rubefacients containing salicylates may be efficacious in acute pain and moderately to poorly efficacious in chronic arthritic and rheumatic pain.7  A systematic review found that preparations containing 0.025% capsaicin were significantly superior to placebo for musculoskeletal pain.8

There is little evidence to support the efficacy of heating pads/wraps and cold packs.In the treatment of acute neck or low back pain, cold and heat therapies have demonstrated limited effectiveness.9

REFERENCES

1. Hadgraft J, Whitefield M, Rosher PH. Skin penetration of topical formulations of ibuprofen 5%: an in vitro comparative study. Skin Pharmacol Appl Skin Physiol 2003; 16: 137–142.
2. Mason L, Moore RA, Edwards JE, et al. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BMC Musculoskelet Disord 2004; 19; 28–35.
3. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004; 329: 324–329.
4. Wiffen PJ, Kalso EA, et al. Topical analgesics for acute and chronic pain in adults - an overview of  Cochrane Reviews.  Cochrane Database Syst Rev. 2017 May 12;5:CD008609. doi: 10.1002/14651858.CD008609.pub2.
5. Bandolier Extra. Topical analgesics: a review of reviews and a bit of perspective. March 2005. (http: //www.jr2.ox.ac.uk/bandolier/Extrafrobando/Topextra3.pdf)
6. Underwood M, et al. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study. BMJ 2008; 336: 138–142.
7. Mason L, Moore RA, Edwards JE, et al. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ 2004; 328: 998–1001.
8. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 2004; 328: 991–995.
9. McCarberg B,D'Arcy Y. Options in topical therapies in the management of patients with acute pain. Postgrad Med.2013;125(4 Suppl 1):19-24.