Antidepressants are a heterogeneous group of drugs which have all demonstrated beneficial activity for patients with major depressive order. Additionally, these agents may have beneficial effects in patients with anxiety disorders (e.g. panic disorder, generalized anxiety disorder, social anxiety, post-traumatic stress disorder, and obsessive–compulsive disorder), eating disorders, attention deficit hyperactivity disorders, premenstrual dysphoric disorder, and chronic pain. Many antidepressants possess analgesic qualities for a broad range of pain conditions independent of their effects on mood.

Antidepressant medications may be classified as follows (Smith 2007):

Although the role of SSRIs in providing effective analgesia is uncertain, it appears limited at best (Saarto and Wiffen 2007). Two classes of antidepressants have significant analgesic properties, the TCAs, and SNRIs. Both TCAs and SNRIs (e.g., venlafaxine) have NNT roughly in the neighborhood of three (Saarto and Wiffen 2007).

Most potent effects on the noradrenergic system is desipramine [also going along with it being least sedating] (nortriptyline also exhibits preferential inhibition of NE reuptake over 5-HT reuptake). Doxepin has the most potent anti-histaminergic effects.

The TCAs can be divided into amines and their demethylated secondary amine derivatives. In addition, maprotiline (Ludiomil) is classified as a tetracyclic.

The tertiary amine TCAs include the following:

The secondary amine TCAs include the following:

TCAs, although having reasonable analgesic properties, may also possess multiple undesirable adverse effects. These adverse effects may vary depending on the individual agent. Among the TCAs, amitriptyline has the most potent anticholinergic effects and desipramine has the least, and thus is the least sedating.

Multiple placebo-controlled RCTs have found TCAs to be efficacious for several different types of neuropathic pain (Dworkin et al. 2007; Finnerup et al. 2005, 2007, 2010; Saarto and Wiffen 2007; Sindrup et al. 2005). In addition, TCAs are efficacious for the treatment of depression, a common comorbidity in patients with chronic pain, but the analgesic efficacy in neuropathic pain has been established in nondepressed patients, which establishes their beneficial effect in neuropathic pain cannot be explained simply by antidepressant effects. Anticholinergic adverse effects are common and include dry mouth, orthostatic hypotension, constipation, and urinary retention. These effects can be reduced by starting with low dosages administered at bedtime and with slow titration to higher dosage as well as by using a secondary amine TCAs (e.g., nortriptyline or desipramine).

The Neuropathic Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) developed guidelines which recommend prescribing TCAs, with caution in patients with ischemic cardiac disease or ventricular conduction abnormalities, limiting the dosages to less than 100 mg/day when possible and obtaining a screening electrocardiogram for patients older than 40 years (Dworkin et al. 2007).

It can take up to 6–8 weeks, including 2 weeks at the highest dosage tolerated, for an adequate trial of treatment with TCA however, analgesia tends to be evident quicker (after about a week) and at lower does than when these agents are utilized to treat depression (Dworkin et al. 2007; Finnerup et al. 2005).

There are four SNRIs available in the United States. Venlafaxine (Effexor) and Desvenlafaxine (Pristiq) are FDA-approved for the treatment of major depressive disorder. Milnacipran is FDA-approved for the treatment of fibromyalgia. Duloxetine and venlafaxine are selective SNRIs that have been studied in peripheral neuropathic pain (another SNRI, milnacipran has been studied only in fibromyalgia).

Venlafaxine has shown efficacy in painful diabetic peripheral neuropathy and painful polyneuropathies of different origins, but not in postherpetic neuralgia (Dworkin et al. 2007). Typically 2–4 weeks are required to titrate to an efficacious dosage (that is 150–225 mg/day); venlafaxine is available in short- and long-acting preparations. At very low doses, venlafaxine tends to “act” more like an SSRI but is clearly an SNRI as the dose is increased. Cardiac conduction abnormalities have been reported in a small number of patients, and blood pressure increases can occur; therefore venlafaxine should be prescribed with caution in patients with cardiac disease. In addition, venlafaxine should be tapered when treatment is being discontinued because of withdrawal symptoms.

The U.S. Food and Drug Administration approved duloxetine hydrochloride to treat chronic musculoskeletal pain on November 4, 2010, including discomfort from osteoarthritis and chronic lower back pain. Cymbalta was first used to treat major depressive disorder in 2004. Since its initial approval, over 30 million patients in the United States have used duloxetine. It was approved for the treatment of diabetic peripheral neuropathy in 2004; generalized anxiety disorder and maintenance treatment of major depression in 2007; and fibromyalgia in 2008. More than 29,000 patients have used duloxetine in clinical trials, and more than 600 patients were studied in the clinical trials involving osteoarthritis and CLBP. The safety evaluation for duloxetine included review of data from the clinical trials as well as postmarketing data from the previously approved patient populations. The FDA assessed the efficacy of duloxetine in CLBP and osteoarthritis in four double-blind, placebo-controlled, randomized clinical trials. At the end of the study period, patients taking duloxetine had a significantly greater pain reduction compared with placebo. The most common side effects reported with duloxetine include nausea, dry mouth, insomnia, drowsiness, constipation, fatigue, and dizziness. Other serious side effects include liver damage, allergic reactions such as hives, rashes and/or swelling of the face, pneumonia, depressed mood, suicide, suicidal thoughts and behavior.

Skljarevski et al. (2010) conducted a randomized, double-blind, placebo-controlled study; and assessed efficacy and safety of duloxetine in patients with CLBP. Adults (n  =  401) with a nonneuropathic CLBP and average pain intensity of ≥4 on an 11-point numerical scale (Brief Pain Inventory [BPI]) were treated with either duloxetine 60 mg once daily or placebo for 12 weeks. The primary measure was BPI average pain (Skljarevski et al. 2010). Compared with placebo-treated patients, duloxetine-treated patients reported a significantly greater reduction in BPI average pain (p  ≤  0.001). Similarly, duloxetine-treated patients reported significantly greater improvements in PGI-I, BPI-S, BPI-I, 50% response rates, and some health outcomes. The RMDQ and 30% response rate showed numerical improvements with duloxetine treatment. Significantly more patients in the duloxetine group (15.2%) than patients in the placebo group (5.4%) discontinued because of adverse events (p  =  0.002). Nausea and dry mouth were the most common treatment-emergent adverse events with rates significantly higher in duloxetine-treated patients (Skljarevski et al. 2010).

Duloxetine has shown consistent efficacy in painful polyneuropathy (DPN) (Dworkin et al. 2007) with effectiveness sustained for 1 year in an open label trial (Raskin et al. 2006). Unfortunately, Duloxetine has not been studied in any other types of neuropathic pain and so its efficacy in such conditions is unknown. The most common adverse affect of Duloxetine is nausea, which seems to be reduced by administering 30 mg once daily for 1 week before increasing to 60 mg once daily. Duloxetine does not seem to produce clinically important electrocardiographic or blood pressure changes and our recent review concluded that aminotransferase monitoring is unnecessary.

The 5% lidocaine patch has shown efficacy and excellent tolerability in trials involving patients with postherpetic neuralgia and allodynia and in patients with allodynia due to different types of peripheral neuropathic pain (Davies and Galer 2004; Khaliq et al. 2007). As a topical treatment without substantial systemic absorption, the most common adverse effects are mild local reactions. The lack of systemic adverse affects and drug interactions can be particularly advantageous in all the patients or patients with complex neuropathic pain. Lidocaine gel (5%), which is less expensive than the lidocaine patch, has also shown efficacy in patients with postherpetic neuralgia and allodynia. Topical lidocaine is most appropriate in well-localized neuropathic pain and is likely to be of benefit in patients with central neuropathic pain. Unfortunately, attempts to predict which patients are most likely to respond to this treatment with topical lidocaine have been generally unsuccessful.

Capsaicin is an alkaloid derived from chili peppers; repeated application is thought to lead to depletion of substance from primary afferent neurons (Lee et al. 1991). The main disadvantage of capsaicin is the initial burning sensation, which may persist for days. Capsaicin must be applied 3–4 times per day over the entire painful area for up to 6–8 weeks before optimal pain relief can be achieved. Mason et al. (2004a) reviewed the clinical trial evidence for capsaicin, including six trials in neuropathic pain and three trials in musculoskeletal conditions. They found that 57% of patients with neuropathic pain achieved at least 50% pain relief with capsaicin, compared with 42% of patient of placebo; for patients with musculoskeletal conditions, the capsaicin response was 38 vs. 25% for placebo (Mason et al. 2004a). Approximately one-third of the patients experienced local adverse events with capsaicin.

Derry et al. (2009) performed a Cochrane review that included six studies (389 participants in total) which compared regular application of low-dose (0.075%) capsaicin cream with placebo cream; the NNT for any pain relief over 6–8 weeks was 6.6 (4.1–17). Two studies (709 participants in total) compared a single application of high-dose (8%) capsaicin patch with placebo patch; the NNT for ≥30% pain relief over 12 weeks was 12 (6.4–70). Local skin reactions were more common with capsaicin, usually tolerable, and attenuated with time; the NNH for repeated low-dose application was 2.5 (2.1–3.1) (Derry et al. 2009).

Massey et al. (2010) performed a Cochrane Review of topical NSAIDs for acute pain in adults. Forty-seven studies were included; most compared topical NSAIDs in the form of a gel, spray, or cream with a similar placebo, with 3,455 participants in the overall analysis of efficacy. For all topical NSAIDs combined, compared with placebo, the number needed to treat to benefit (NNT) for clinical success, equivalent to 50% pain relief, was 4.5 (3.9–5.3) for treatment periods of 6–14 days. Topical diclofenac, ibuprofen, ketoprofen, and piroxicam were of similar efficacy (Massey et al. 2010).

A high concentration (8%) capsaicin patch has been studied in multiple RCTs in patients with postherpetic neuralgia (Backonja et al. 2008, 2010; Irving et al. 2011) and reviewed (Jones et al. 2011). A single high-concentration capsaicin patch application utilized to provide analgesia for patients with painful HIV neuropathy resulted in a mean pain reduction of 22.8% during weeks 2–12 as compared to a 10.7% reduction for controls (p  =  0.0026, Simpson et al. 2008). One-third of high-concentration capsaicin patch-treated patients reported ≥30% pain decrease from baseline as ­compared to 18% of controls (p  =  0.0092). Self-limited, mild-to-moderate local skin reactions were commonly observed (Simpson et al. 2008). However, in a second HIV neuropathy trial, the effects of high concentration capsaicin patches did not meet the primary endpoint of the study (Noto et al. 2009).

Application of the high-concentration capsaicin patch in patients with postherpetic neuralgia appears to be safe and well tolerated, and adverse effects were limited to transient increases in pain, as well as location reactions associated with patch application (e.g., application site reactions [pain, erythema]). After a single 1-h application (Webster et al. 2010), the high concentration capsaicin patch may be associated with some sustained reductions in pain that persist for 2–3 months. Simpson et al. (2010) concluded that repeated treatments administered over a 1-year period are generally safe and well tolerated.