Pharmacy & Therapeutics - March 2008 - (Page 174) CONTINUING EDUCATION CREDIT controversial, these agents should not be withheld simply because a person is older. Common side effects of opioids include constipation, nausea, and sedation. Preventive measures may reduce these complications. Tramadol, a nonnarcotic analgesic, is also associated with nausea, constipation, and sedation, but it is generally better tolerated than opioids. The topical agents capsaicin and lidocaine produce minimal systemic side effects. Capsaicin may cause transient burning at the application site, but it is tolerable for most patients. Ease of application and lack of drug interactions make topical products an attractive treatment option for older patients. Table 12 Rational Polypharmacy for Diabetic Peripheral Neuropathic Pain Add-On α-2Δ ligands Opioids Topical agents SNRIs TCAs Opioids Tramadol Topicals α-2Δ ligands Opioids Topicals SNRIs α-2Δ ligands TCAs Topicals α-2Δ ligands Topicals SNRIs α-2Δ ligands TCAs Opioids Tramadol Topicals Avoid Other SNRIs TCAs Tramadol Other α-2Δ ligands Treatment Monitoring SNRIs Tramadol Other opioids Many drugs used to treat DPN are gradually titrated; therefore, frequent monitoring is desired. Pain control should be assessed at each visit. Attention should be paid to improvements (or the lack thereof) and to physical and social functioning. If the agent does not provide adequate relief, changing to another first-line medication is reasonable. If the next agent is not effective or if maximizing the dose is not an option, combination treatment may be warranted. SNRIs TCAs None Combination Treatment Ideally, a single agent should be adequate in providing pain relief. Because of the multiple mechanisms causing DPN, partial effects to monotherapy are to be expected. In fact, only about 70% of patients with neuropathic pain actually respond to a single agent.43,63 Therefore, the use of agents with dif ferent mechanisms of action may provide substantial relief. Despite a lack of controlled data with combination first-line therapies, several recommendations may be made, as presented in Table 12. Patients should be warned that pain relief may occur at the expense of additional side effects. Rationale for polypharmacy: • to decrease toxicity • to address treatment failures • to take advantage of complementary mechanisms of action • to decrease drug–drug interactions SNRI = serotonin–norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant. Adapted with permission from Argoff CE, Backonja MM, Belgrade MJ, et al. Mayo Clinic Proceedings 2006;81(4 Suppl):S12–S25.6 Conclusion Diabetic peripheral neuropathy is a devastating complication of diabetes mellitus that causes significant morbidity and mortality. The pain associated with DPN is described as excruciating by some and may be lessened or relieved by a variety of agents. Much evidence exists to support the use of duloxetine, oxycodone, pregabalin, and TCAs as first-line therapies. However, patients who find these therapies inadequate for pain relief may require an additional agent. Therefore, practitioners should become familiar with the many therapies available to treat patients with DPN, including their mechanism of action, adverse effects, recommended doses, and the available clinical evidence. Sedation associated with these agents may be useful therapeutically; however, it is advisable to titrate the dose slowly. If the anticholinergic effects are pronounced, desipramine should be considered, because it is associated with fewer such effects. The side effects from other antidepressants used for DPN, such as venlafaxine, duloxetine, and other selective serotonin reuptake inhibitors (SSRIs) are not more pronounced in the elderly; therefore, dose adjustments are not required. Dizziness and somnolence are commonly seen with the antiepileptic agents.62 These effects are experienced by all age groups and may be overcome if the dose is slowly titrated. Gabapentin, pregabalin, oxcarbazepine, and topiramate doses may need to be decreased if renal function is impaired. Topiramate may cause weight loss, which may be undesirable in the elderly. Although multiple daily dosing is required for gabapentin, drug interactions are minimal. Although the use of opioids for neuropathic pain remains References 1. Duby JJ, Campbell RK, Setter SM, et al. Diabetic neuropathy: An intensive review. Am J Hosp Pharm 2004;61:160–173. 2. American Diabetes Association. Standards of Medical Care in Diabetes 2007. Diabetes Care 2007;30(Supp 1):S4–S41. 3. Tseng CH. Prevalence of lower-extremity amputation among patients with diabetes mellitus: Is height a factor? Can Med Assoc J 2006;31:174(3):319–323. 4. Head KA. Peripheral neuropathy: Pathogenic mechanisms and alternative therapies. Altern Med Rev 2006;11(4):294–329. 5. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves 174 P&T® • March 2008 • Vol. 33 No. 3
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