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Tricyclic Antidepressants in Post-SCI 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.

Table 25 Tricyclic Antidepressants in Post-SCI Pain

Author Year;

Country

PEDro Score

Research Design

Total Sample Size

MethodsOutcome
Amitriptyline
Agarwal & Joshi, 2017

India

RCT

PEDro=6

N=147

Population: Age=18+ yr; Gender: males=136, females=11; Level of injury: paraplegia=64, tetraplegia=83; Severity of injury: AIS A=112. B/C/D=35; Type of pain=neuropathic.

Intervention: Participants with neuropathic pain (NP) were randomized to either amitriptyline or lamotrigine for 3 wk trials to compare the effects of pain suppression.

Outcome Measures: Short-form MC Gill Pain Questionnaire (SFMPQ2) score on pain, adverse events and withdrawn patients.

1.     No significant differences between reduction of pain scores between the amitriptyline and lamotrigine groups (p>0.05).

2.     Only notable adverse events were dry mouth and drowsiness, and patients reported exceeding the 50 mg dose recommendation in the amitriptyline group with no adverse events in the lamotrigine group.

3.     140 of the 147 subjects completed the study, 5 dropped out and two passed away.

Rintala et al. 2007

USA

RCT

PEDro=10

N=38

Population: SCI: Mean age=42.6 yr; Gender: males=20, females=2; Level of injury: paraplegia=7, tetraplegia=12; Severity of injury: AIS A-C=19, D=3; Time since injury=12.6 yr; Duration of pain=7.3 yr. Type of pain=neuropathic.

Treatment: Patients were randomized into one of six groups: 1) gabapentin-amitripyline-diphenhydramine (GAD; n=7); 2) GDA (n=6); 3) AGD (n=6); 4) ADG (n=6); 5) DGA (n=7); 6) DAG (n=6). Each drug was administered for 9 wk with one washout week before and after each drug treatment, for a total of 31 wk. The maximum doses were 50mg 3x/day for amitriptyline, 1200mg 3x/day for gabapentin, and 25mg 3x/day for diphenhydramine (control).

Outcome Measures: Center of Epidemiologic Studies Depression Scale-Short Form (CESD-SF)

1.     Amitriptyline was significantly more effective than diphenhydramine at 8 weeks, in subjects with high (≥ 10) baseline CESD-SF scores (p=0.035).

2.     No significant difference was seen at 8 weeks in subjects with high (≥ 10) baseline CESD-SF scores in :

·       Effectiveness of amitriptyline over gabapentin (p=0.061).

·       Effectiveness of gabapentin over diphenhydramine (p=0.97).

3.     Subjects with low (<10) baseline CESD-SF scores showed no significant difference among the medications.

Cardenas et al. 2002

USA

RCT

PEDro=9

N=84

Population: Mean age=41 yr; Gender: males=80%, females=20%; Level of injury: cervical, lumbar; Severity of injury: AIS: A-D; Time since injury=169 mo. Type of pain=.europathic and musculoskeletal.

Treatment: Subjects with chronic pain randomized to a 6 wk course of amitriptyline or placebo 1-2 hr before bedtime.

Outcome Measures: Average pain measure (scale 0-10), Short form McGill Pain Questionnaire (SF-MPQ), Brief Pain Inventory (BPI), Center of Epidemiologic Studies Depression Scale (CESD) , Functional Independence Measure  (FIM).

1.     There were no significant differences between the two groups at baseline and at the 6 wk time period for any of the measures except satisfaction with life which showed higher scores for those in the placebo group (p=0.004).

2.     For those who remained on the two medications, it was noted that those in the amitriptyline group had significantly higher severity ratings for increased spasticity (p=0.005) than those in the control group.

Duloxetine
Vranken et al. 2011

Netherlands

RCT

PEDro=9

N=48

Population: Age=53 yr; Type of pain=neuropathic.

Intervention: Participants were randomized to one of two groups: flexible dose placebo who received 1-2 capsules a day or placebo.

Outcome Measures: Visual Analogue Scale (VAS)

1.     A two-point reduction on VAS in pain intensity was seen in the duloxetine group after 8 wk of treatment.

2.     A decrease in pain was seen in the duloxetine group compared to the control group (p=0.05).

3.     No significant between group differences were seen in SF-36.

Venlafaxine
Richards et al. 2015

USA

RCT

PEDro=9

N=123

Population: Mean age=40yr; Gender: males=99, females=34; Time since injury=10.9yr. Type of pain=neuropathic, nociceptive, or mixed.

Treatment: Participants were randomized to receive either venlafaxine or placebo.  The treatment group received a starting dose of 37.5mg/d which was titrated up to a max of 225mg/d by week 6 if tolerated.  Doses could be increased by another 300mg at week 10 if needed to treat depression.

Outcome Measures: Numeric Rating Scale (NRS)

1.     No significant improvement in pain related outcomes were seen among those with neuropathic or mixed pain.

2.     Individuals with nociceptive pain reported significant improvement in outcomes including: pain intensity (p=0.018) and pain interference subscales general activity (p=0.018), mood (p=0.048), mobility (p=0.005), normal work (p<0.001), relations with other people (p=0.021), sleep (p=0.014), and enjoyment of life (p=0.017).

Trazodone
Davidoff et al. 1987b

USA

RCT

PEDro=6

Initial N=19; Final N=18

Population: Mean age=39 yr; Gender: males=16, females=2; Time since injury=49 mo. Type of pain=neuropathic.

Treatment: Subjects underwent a 2 wk placebo lead-in period with a 6 wk randomization to 150 mg trazodone per day or placebo.

Outcome Measures: McGill Pain Questionnaire (MPQ), Sternbach Pain Intensity (SPI), Zung Pain and Distress Index (PAD)

1.     No significant differences were noted between the groups on MPQ, SPI, or PAD.

2.     More subjects reported side effects in the experimental group (p<0.05).

3.     More subjects in the placebo group completed the 8 wk study (p<0.01).

Discussion

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.

Conclusion

There is level 1b evidence (from one randomized controlled trial; 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 randomized controlled trial; Vranken et al. 2011) that duloxetine may improve neuropathic pain post SCI.

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

Amitriptyline is effective in reducing neuropathic pain in depressed SCI individuals.

Amitriptyline is no more effective as lamotrigine in improving pain post SCI.

Duloxetine may improve neuropathic pain post SCI.

Trazodone does not reduce post-SCI neuropathic pain.