Each month, Dr. Lynette Menefee tackles pressing issues in pain management with one of the nation's leading practitioners. This month, Dr. Menefee speaks with Charles E. Argoff, M.D., Director of the Cohn Pain Management Center at North Shore University Hospital in Manahasset, NY. Dr. Argoff is also an Assistant Professor of Neurology at the New York University School of Medicine. Dr. Argoff speaks with us this month about targeted peripheral analgesics.

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Questions

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Dr. Lynette Menefee: Thanks for taking the time to talk with us about targeted peripheral analgesics, Dr. Argoff.

First, will you define these agents and give us some examples of drugs in this class?

Charles E. Argoff, MD: The term targeted peripheral analgesics has been developed to describe those medications whose mechanism of action lies primarily at the level of the peripheral (as opposed to central) nervous system. More specifically, the term is most often applied to those analgesic agents that in the past might have been called “topical” agents. Examples of such agents include the lidocaine 5% patch, capsaicin, and the eutectic mixture of lidocaine and prilocaine. The recent discovery that tricyclic antidepressants possess notable local anesthetic-like activity has led to several preliminary investigations of these agents, primarily amitriptyline and doxepin as peripheral analgesics applied topically.

LM: What do you see as the clinical advantages to targeted peripheral analgesics? Are there disadvantages to these agents?

CA: One of the clear advantages of the targeted peripheral analgesics is that, in contrast to conventional systemically administered analgesics, the use of these is less likely to be associated with systemic side effects. Insignificant serum levels of the medication are required to produce the analgesic effect. Assuming that both types of agents are effective in reducing pain for a given person and condition, the relative lack of systemic side effects may be key to the successful management of that person’s pain. Dose related side effects often limit the benefit of other analgesics. As a result, significant drug-drug interactions are not experienced. A targeted peripheral analgesic may also have indirect central activity by reducing the amount of peripheral pain producing information that the central nervous system needs to process. Finally, if a person is complaining of pain over the thorax for example, a targeted peripheral analgesic may be applied directly over the painful site. On the other hand, there may be certain painful conditions for which a systemic mechanism of action would be required or at the very least helpful in reducing the pain. Examples of such might include central post-stroke pain or spinal cord injury pain. For other painful states in which there are likely both peripheral and central nervous system pain mechanisms present (e.g., post-herpetic neuralgia or the complex regional pain syndromes), a patient may actually benefit more from the combined use of a targeted peripheral analgesic with a systemically administered analgesic rather than either alone.

LM: It’s my understanding that these medications are primarily used for neuropathic pain like postherpetic neuralgia (PHN) or diabetic neuropathy. Is this true? If so, which agents have been found most helpful?

CA: It is certainly true that the earliest use of these medications had been for the treatment of neuropathic pain, specifically for the treatment of PHN. In fact, the lidocaine 5% patch was originally FDA approved for PHN and it was the first medication of any type to be FDA approved for PHN. Soon after the use of these medications for PHN, several studies demonstrated that the use of the lidocaine patch as a targeted peripheral analgesic could successfully reduce the pain associated with other neuropathic pain states (in an off-label manner) such as painful diabetic neuropathy, complex regional pain syndrome, and post-mastectomy pain. The use of topical doxepin has also been explored in the treatment of neuropathic pain with good results noted as well.

LM: What other types of pain respond to targeted peripheral analgesics?

CA: Recently, several open label studies have been completed which have strongly suggested that other non-neuropathic pain states may respond to targeted peripheral analgesics. The conditions include acute, subacute and chronic low back pain, myofascial pain syndrome, and osteoarthritis of the knee. In each of these studies, the lidocaine 5% patch was the targeted peripheral analgesic. Anectodotally, I am aware of the use of the lidocaine 5% patch by one of the NBA teams for the treatment of acute sprains and strains experienced while playing basketball. The successful use of the lidocaine 5% patch has also been reported in an uncontrolled study of post-operative pain. The use of capsaicin has been studied in the management of osteoarthritis and it has been reported that various anti-inflammatory agents are being studied for their potential use as a targeted peripheral analgesic.

LM: How should practitioners decide whether to use a targeted peripheral analgesic agent?

CA: Practitioners should first be comfortable with the type of pain disorder that they are treating. Next they need to recognize the emerging data regarding the usefulness of these types of agents in the management of various types of pain disorders including those with both peripheral and/or central etiologies. Practitioners should recognize that these agents are among the safest and most effective approaches to pain control currently available. They should therefore strongly consider using these agents as first line therapies alone or in combination with a systemic agent depending on the individual situation. It may take several weeks of regular use of a targeted peripheral analgesic before the full analgesic effect will be realized and clinicians need to know that so they can appropriately advise their patients regarding such. Finally, no matter how effective an agent may be, it rarely, if at all, reduces pain completely; therefore, medications, both targeted peripheral analgesics and systemic agents may need to be combined rationally (“rational polypharmacy”). Additionally, the patient needs to know that the goal of treatment is to reduce pain to a manageable level to achieve functional restoration whenever feasible and not to reduce pain to zero (although in an ideal world that would be possible!). As an example of this, a recent study demonstrated that for 3 painful conditions, low back pain, PHN and painful diabetic neuropathy, the addition of the lidocaine 5% patch to a treatment regimen that already included gabapentin reduced pain further in all three conditions.

LM: Is there anything specific that practitioners should know about the Lidocaine 5% patch?

CA: As an example of a targeted peripheral analgesic, it is clearly the most widely studied. A multitude of painful conditions have been shown to be responsive to this medication as noted in my previous comments and it has also been shown to be an extremely safe medication. Application site sensitivity has been the most commonly reported side effect. If this does occur and if it persists, the patient should be advised to discontinue use of this drug. Serious side effects are extremely rare if at all reported. Although the FDA approval for its use in PHN is for the use of 3 patches to be applied to the painful sites 12 hours of each day, many studies have now confirmed the safety and efficacy of the lidocaine 5% patch use when up to 4 patches are used for up to 24 hours/day. This may be especially clinically relevant in certain pain states in which the patient may benefit from more continuous application of the lidocaine 5% patch.

LM: Do you have other advice for clinicians about using targeted peripheral analgesics?.

CA: As would be true for any other group of pharmacologic agents, the clinician must rely on published data regarding safety and efficacy, drug-drug interactions, tolerability and cost in advising his/her patients regarding which analgesics and in particular which targeted peripheral analgesic to use. Currently, it is fairly clear that the lidocaine 5% patch has been widely studied, has been shown to be safe and efficacious for many pain types, is associated with few drug-drug interactions and is well tolerated by patients. In contrast, other agents such as capsaicin, are associated with poor tolerability and inconsistent efficacy. The use of topical antidepressants is not well studied. It would therefore seem prudent to consider the lidocaine 5% patch as the targeted peripheral analgesic of choice at this time.

LM: Thanks so much for taking the time to talk with us.