Tricyclic Antidepressants for Pain

Tricyclic antidepressant drugs are thought to modulate pain by inhibiting the uptake of norepinephrine and serotonin in the CNS. Sandford et al. (1992) have suggested that the tricyclic antidepressants exert an analgesic effect by making more serotonin available in the CNS, thereby potentiating the inhibitory action of the dorsal horn of the spinal cord. Unfortunately, these medications are often sedating and produce a variety of anticholinergic side effects.

The partial effectiveness of tricyclic antidepressants (TCA) in some SCI patients with dysesthetic pain suggests that this drug is simply affecting the pain by treating the depression. Sandford et al. (1992) noted that pain and depression maybe chemically linked. Depression can lower pain thresholds or pain tolerances thereby increasing the patient’s experience of pain. However, Max et al. (1987) were able to show that TCA had analgesic properties despite low doses or short treatment cycles with analgesic activity occurring independent of mood changes.

Davidoff et al. (1987b) reported trazodone’s lack of effectiveness in relieving pain in 19 SCI patients with chronic dysesthetic pain, using a double-blind placebo controlled trial. Trazodone reportedly selectively inhibits serotonin and norepinephrine uptake in a ratio of 25:1, and is thought to produce greater analgesia and less anticholinergic side-effects compared to non-selective agents such as amitriptyline.


Tricyclic antidepressants are often recommended for the treatment of neuropathic pain following non-SCI causes. Therefore, it is important to study the use of tricyclic antidepressants in the treatment of post-SCI pain. Agarwal and Joshi (2017) found no significant difference in pain reduction between amitriptyline or lamotrigine. Cardenas et al. (2002) reported no significant difference in randomized spinal cord injury patients receiving either amitriptyline or placebo given 1-2 hours before bedtime for a period of six weeks. Heilporn (1978) using combinations of melitracin and TENS reported relief of pain in eight of eleven SCI patients with dysesthetic pain. Vranken et al. (2011) found individuals receiving duloxetine reported clinically significant (>2 units on VAS) improvement on pain compared to those in a placebo control group. In an interesting study by Rintala et al. (2007), amitripyline was no better than gabapentin in depressed and non-depressed subjects but was better than diphenhydramine for depressed subjects only.

Davidoff et al. (1987b), in a six week double-blind placebo-controlled trial, found that trazodone was ineffective at relieving pain in 18 SCI patients with chronic neuropathic pain.


There is level 1b evidence (from one RCT: Rintala et al. 2007) that amitriptyline is effective in the treatment of post-SCI neuropathic pain in individuals only when there is concomitant depression.

There is level 1b evidence (Agarwal & Joshi 2017) that amitriptyline is no more effective as lamotrigine in improving pain post SCI.

There is level 1b evidence (from one RCT: Vranken et al. 2011) that duloxetine may improve neuropathic pain post SCI.

There is level 1b evidence (from one RCT: Davidoff et al. 1987b) that trazodone does not reduce post-SCI neuropathic pain.

Chapter Downloads