Pain is an unpleasant sensory emotional experience associated with actual or potential tissue damage, as defined by the World Health Organization.1 Chronic pain can have a detrimental effect on quality of life and daily activities and is one of the main causes of physical disability in the United States and Europe affecting more than 30% of people worldwide.2,3
Written by Karina Oganezova, Trinity College Dublin, Professor Connail McCrory, Trinity College Dublin and Dr Deborah Galvin, Trinity College Dublin
Topical as route of administration
Topical analgesic regimes provide pain relief without the burden of the systemic side effects seen with other routes of delivery. They are a targeted therapy that act peripherally on nociceptor pathways at the location of the pain.4 Reduced systemic absorption results in low plasma levels of the therapeutic drug leading to a reduced risk of systemic side effects such as respiratory depression, sedation, nausea and delirium.4,5,6,7,8 The use of oral opioid-based analgesics has resulted in high rates of abuse and addiction, with thousands dying from overdoses.4 Topically administered opioids are beneficial in this regard, having a lower risk of addiction and diversion compared to oral preparations.9
The method of preparation is important to ensure adequate application of the active component. The major methods of achieving this are by causing the active drug to be a solute in a stable preparation most composed of alcohol, sorbitol and stearate for stability. An example of this is capsaicin cream and NSAID preparations. Steroid preparations such as budesonide are stable in paraffin wax solvents as are immunosuppressive preparations such as tacrolimus. The advantage of the paraffin wax solvents is stickiness to the skin as opposed to the alcohol preparations which are easily rubbed off by clothing. The patch method of application is more complex involving an aqueous base in the case of lignocaine with preservatives such as methylparaben and propylparaben. The matrix fentanyl membrane transdermal patch is contained in silicone with a rate-controlling membrane which maintains constant serum fentanyl concentrations throughout its application, proving to be highly important due to fentanyl’s action as a potent respiratory depressant.10
Local Anaesthetics
The lidocaine 5% medicated plaster is used as a second line treatment for peripheral neuropathic pain as well as postoperative pain management.5,11,12 Additionally capsaicin, an active component of chili peppers, is used as a topical analgesic.11,13 Capsaicin binds to nociceptors in skin that are responsible for burning, itching, or prickling; constant or high exposure to capsaicin can result in desensitization of these receptors, resulting in these nerve terminals unable to conduct an action potential.13 Low dose topical capsaicin creams have not been shown to be effective in neuropathic pain due to its burning sensation, often limiting the number of times it can be applied. Due to this, a high concentration capsaicin cutaneous patch (HCCP) has been introduced to allow a one-time application and was shown to be non-inferior to oral pregabalin in an open label randomized trial.13
Opioids
Buprenorphine is used for chronic arthritic pain in frail patients and fentanyl, which is a strong opioid, is traditionally used for cancer pain relief. Buprenorphine is a semi-synthetic partial µ-opioid receptor agonist and κ- and δ-opioid receptor antagonist that is accompanied with less respiratory depression and sedation. Fentanyl is a synthetic µ-opioid receptor agonist with fast receptor association and dissociation characteristics but is more potent and addictive. Both agents are available as transdermal formulations and penetrate the skin effectively due to their low molecular mass, high lipid solubility and high potency. The fentanyl patch is the treatment of choice for patients with cancer pain in metastatic disease who are unable to swallow or have poor compliance.14
Steroids and NSAIDs
Topical corticosteroids are safe and inexpensive agents commonly used for skin conditions; however, studies have published the effectiveness of these agents as a treatment for osteoarthritis. Although the European League Against Rheumatism suggests NSAID topical therapy as first line choice, there is evidence of inflammation being a potential treatment target in hand osteoarthritis, which could be effectively treated by glucocorticoids.15 Topical NSAID’s like diclofenac and ketoprofen, capsaicin cream, and civamide cream are also used for treatment of osteoarthritis.16
Neuropathic Pain
Peripheral neuropathic pain in conditions such as: post-traumatic neuralgia, post-herpetic neuralgia, painful diabetic neuropathy, and HIV-related neuropathy are indications for topical analgesia.1,11 Surgically-induced neuropathic pain affects 2-10% of individuals following surgery, and is characterized by sensory loss followed by hypersensitivity to pain, resistance to medication, and more likely to become chronic.13 This pain can vary based on surgical factors; for example, about half of patients with chronic pain postthoracotomy are believed to have neuropathic components.13 Although the recommended first line treatments for these conditions are oral medicines such as tricyclic antidepressants, anticonvulsants, and SSRI’s, topical agents may be more beneficial due to its localized activity and minimal systemic effects.1,11
Other conditions
Eczema is a type of dermatitis that causes dry, itchy and inflamed skin. Low-potency corticosteroids such as hydrocortisone and moderate-potency corticosteroids such as methylprednisolone are topical treatments used for management of eczema.17
Psoriasis is a chronic inflammatory autoimmune skin condition in which the immune system regards normal skin cells as an infection, producing dry, red plaques on the skin. Although it is incurable, there are treatments that manage the condition. One of these treatments is protopic 0.1% ointment, also known as tacrolimus, which is an immunosuppressant licensed for atopic dermatitis. It is often prescribed off-label to treat psoriasis on the face or genitals, due to its ability to suppress the immune system, thereby stopping the hyperproduction of skin cells.18
Complications with use
Although the use of topical agents is accompanied by many advantages in comparison to oral agents, there are several complications that need to be addressed. Using patches may require the need to apply adhesive tapes or bandages to secure the patch into place and this may be problematic for the treatment of distal painful neuropathy such as in HIV or diabetic neuropathy involving the feet.1 Topical formulations such as creams, ointments, and gels have removed this burden, however these lack the accuracy of dosing.1 Although topical analgesics are thought to exert analgesia by interacting with peripheral opioid receptors, a degree of systemic absorption has been demonstrated. Some studies have observed significant analgesia, however, it was noted to have occurred within 60 minutes of topical application, therefore not deemed appropriate to deal with wound related breakthrough pain.19 Furthermore, studies have shown topical administration of NSAIDs penetrate through the layers of skin and can potentially lead to systemic absorption. This is especially seen with methyl salicylate which is lipophilic and readily penetrates the skin when applied as a topical agent, and is hydrolysed to salicylic acid in the tissues.2 This can result in the tissues becoming saturated leading to chronic salicylate toxicity, which may cause vomiting, confusion, and hyperventilation leading to respiratory alkalosis.
Conclusion
In conclusion, topical analgesics provide a localized treatment for disorders such as chronic neuropathic pain, chronic arthritic pain, cancer pain, post-surgical pain, wound healing, and diabetic or HIV-associated neuropathy. Due to their ability to bypass the systemic circulation and gastrointestinal system, these agents provide relief without the adverse effects associated with oral analgesics, such as addiction and drug diversion, nausea, vomiting, constipation, drowsiness, and headaches. Overall, they are well tolerated.
