Pharmacy & Therapeutics - March 2008 - (Page 167) CONTINUING EDUCATION CREDIT may lead to diminished blood flow, another major dysfunction in DPN. Finally, increased homocysteine levels, a well-known cause of endothelial dysfunction, are present in many patients with diabetes mellitus.4 In this article, we provide a comprehensive review of the drug therapies commonly used to treat the pain associated with DPN. We also present a stepwise approach to selecting an appropriate agent. 1).9–13 Amitriptyline is the most studied TCA for DPN and has been compared with placebo, imipramine, and desipramine. Amitriptyline, when compared with placebo, reduced pain to a significant degree. Pain relief was evident as early as the second week of therapy, with greater pain relief noted at higher doses (at a mean dose of 90 mg). A decrease in pain was not associated with improvement in mood. A systematic review of the TCAs, including fewer than 200 patients, found no difference in efficacy between the agents.8 Desipramine is associated with fewer adverse events than amitriptyline and is thus the preferred TCA in elderly patients if a TCA is desired. Duloxetine Pharmacological Agents Antidepressants Tricyclic Antidepressants The tricyclic antidepressants (TCAs) are commonly prescribed to treat depression as well as various chronic pain states. These agents appear to relieve pain by blocking the neuronal reuptake of norepinephrine (NE) and serotonin (5-HT), thereby causing more of these neurotransmitters to be available in the synapse.1 The analgesic effects of TCAs seem to be independent of their antidepressant effects.5,6 The adverse effects associated with this class are anticholinergic in nature and include constipation, dizziness, blurred vision, urinary retention, cardiac arrhythmias, and dry mouth.6 Affinities for the muscarinic (cholinergic) receptor vary within this class; amitriptyline has the highest affinity, followed by protriptyline (Vivactil, Merck), clomipramine (Anafranil, Mallinckrodt), doxepin (Sinequan, Pfizer), imipramine (Tofranil, Mallinckrodt), nortriptyline (Pamelor, Mallinckrodt), and desipramine (Norpramin, Aventis). The tertiary amine TCAs (amitriptyline, imipramine, clomipramine, and doxepin) also have the greatest affinity for histamine and alpha1-adrenergic receptors and are associated with more sedation and orthostatic hypotension.7 Although the Food and Drug Administration (FDA) has not approved TCAs for the treatment of DPN,8 the efficacy of these products has been highlighted in many trials (Table Duloxetine HCl (Cymbalta, Eli Lilly) is a potent dual reuptake inhibitor of both 5-HT (serotonin) and norepinephrine (NE), and it has a weak affinity for dopamine, muscarinic, histamine, and other receptors. Subsequently, adverse effects, when compared with those resulting from TCAs, are typically more tolerable and include asthenia, constipation, dizziness, dry mouth, hyperhidrosis, nausea, and somnolence.14 Duloxetine has been an effective therapy for depression in several randomized clinical trials.15–17 In these studies, duloxetine also improved painful symptoms associated with depression. More than 50% of the reduction in painful symptoms was attributed to duloxetine rather than to a secondary effect of improving depression.18 Duloxetine is the first FDA-approved medication indicated for the treatment of DPN. The recommended dose is 60 mg once daily without regard to meals. Higher doses have been shown to be safe and effective, although doses above 60 mg provide little benefit and confer increased adverse effects.19,20 Data from clinical trials involving duloxetine in patients with DPN are summarized in Table 2. In the first published trial, patients’ pain scores began improving as early as the first week of therapy. Patients also reported improvements in body pain and mental health. Duloxetine did not significantly change Table 1 Clinical Trials of Tricylic Antidepressants Reference Max5 Sindrup9 Kvinesdal10 Turkington11 Max12 Max13 No. Design Treatment AMI 25 mg/day (titrated to 150 mg/day) or PBO IMI 125–200 mg/day or PBO IMI 50–100 mg/day or PBO IMI 100 mg/ day, AMI 100 mg/day, or DIAZ 5 mg t.i.d. DES 12.5 mg (up to a mean of 201 mg/day) AMI 12.5 mg (up to 150 mg/day) or DES 12.5 mg (up to 150 mg/day) Study Conclusions Significantly greater pain relief with higher doses of AMI; Ach side effects noted 89% patients reported improvement in pain with IMI; more Ach side effects seen with IMI No difference in symptom score but notable improvement in global assessment Complete pain relief with IMI and AMI; no statistics reported, weak study DES significantly decreased pain intensity; no association with dose or pain relief AMI and DES are superior to PBO in pain relief; more relief noted in AMI group 29 R, DB, PC, CO 9 R, DB, PC, CO 12 R, DB, PC, CO 59 R 20 R, CO, DB 29 R, CO, DB, PC Ach = anticholinergic; AMI = amitriptyline; CO = crossover; DB = double-blind; DES = desipramine; DIAZ = diazepam; IMI = imipramine; PBO = placebo; PC = placebo-controlled; R = randomized; t.i.d. = three times daily. Vol. 33 No. 3 • March 2008 • P&T® 167
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