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Cannabinoids in SCI

Pain

Author Year; Country
Research Design
Score
Total Sample Size

Methods Outcome

Andresen et al. 2016; Denmark
RCT
PEDro = 11
Level 1
N = 73

Population: Mean age=56.3±11.6 yr; Gender: males=54, females=19; Time since injury=10.3±11.7 yr; Level of injury: tetraplegia=32, paraplegia=41; Severity of injury: AIS A=24, B=3, C=15, D=31; Type of pain=neuropathic.
Intervention: Participants were randomized to a ultramicronized palmitoylethanolamide (Normast) group or a placebo group taking dosages 2 times daily with 12 h between dosages, for 12 wks.
Outcome Measures: Numeric Rating scale (0-10) for change in neuropathic pain intensity from baseline wk to wk 12. Secondary outcomes: analysis and effects on spasticity, evoked pain, sleep problems, anxiety, depression and global impression of change.
  1. No significant difference between change in neuropathic pain intensity observed between the Normast and placebo groups (p=0.46).
  2. No significant difference over time between the two groups when using covariates (p=0.82).
  3. Normast group had a significant reduction in their use of rescue medication compared to the placebo group (p=0.02).
  4. Normast group showed a significant increase in intensity of spasticity observed in the pain diary recordings compared to a decrease in the placebo group (p=0.013).
  5. No significant differences observed in any of the other outcome measures (p>0.05).

Wilsey et al. 2016; USA
RCT Crossover
PEDro = 8
Level 1
N = 42 (29 SCI)

Population: Mean age=46.4±13.6 yr; gender: males=29, females=13; Level of injury: C=22, T=14, L=6.
Intervention: Crossover design with placebo, 2.9% and 6.7% THC vapour; 4 puffs at t=0 and 4 puffs at t = 240 min. Treatment periods were 480 min. for each exposure with measurements every 60 min.
Outcome Measures: 11-point pain scale, Patient Global Impression of Change, Neuropathic Pain Scale, VAS allodynia, Heat-pain threshold.
  1. 9% THC group (2nd dose at t = 240 min.):
    1. Pain intensity was significantly reduced at all measurement points (p<0.05, a t = 120/240 min. <0.01).
    2. Pain relief was significantly higher at all measurement points (p<0.0001) except 360 minutes.
    3. All neuropathic pain measures improved except itching at all measurement points (p<0.0001).
  2. 6.7% THC group (2nd dose at t = 240 min.):
    1. Pain intensity was significantly reduced at t = 60, t = 300, t = 360 and t = 420 min. (p<0.05).
    2. Pain relief was significantly higher at all measurement points (p<0.0001).
    3. All neuropathic pain measures improved except itching at all measurement points (p<0.0001).

Rintala et al. 2010; USA
Crossover-RCT
PEDro = 5
Level 2
N = 5

Population: Convenience sample. Mean age: 50.1 yr; Level of injury: paraplegia=4, tetraplegia=3; Level of severity: AIS A=4, B=1, D=2; Mean time since injury:  21.9 yr; Type of pain: neuropathic (>6 months).
Intervention: Participants were randomized into two groups: i) 5 mg dronabinol titrated every third day (max 20 mg/day); ii) 25 mg diphenhydramine day once then titrated up to 75 mg/day.
Participants remained in a 7 day stabilization phase once titration was complete and then a 28 day maintenance phase. After a 9 day down-titration period and 7 day washout period, participants crossed over to the other arm.
Participants stopped all pain medication prior to the study and were allowed break-through medication during the study, consisting of 5mg/325mg oxycodone/acetaminophen max. 8d./24h.
Outcome Measures: Brief Pain Inventory (BPI).

  1. Pain intensity was not significantly different between the dronabinol and diphenhydramine groups (n=5).
  2. Seven people started the study, but 2 participants dropped out during the first round while in the Dronabinol group, one participant due to side-effects and the other unwilling to stop taking dronabinol.
  3. 3 participants used break-through medication during the study. Their patterns of use were occasionally, 2 tablets daily and 8 tablets daily.
  4. No significant difference was seen in side effects between the groups.
  5. Most common side effects included dry mouth, constipation, fatigue and drowsiness.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data.

Hagenbach et al. 2007; Switzerland
Phase 1
Open-label Clinical Trial
N = 15
RCT
PEDro = 4
Level 2
N = 13

Population: SCI (N=15): Age range: 29-66 yr; Gender: males=11, females=2; Level of injury: C4-T11; Level of severity: AIS A,B,C,D; Type of pain: spastic.
Intervention: Phase 1-2: Patients received 10 mg oral tetrahydrocannabinol (THC) on day one. Dose titration began on day two until the maximum tolerated dose or treatment aim was achieved and maintained for 6 wk. Phase 3: In a double-blind design, SCI patients from phase 1 of the study were randomly assigned to either maximum oral THC doses (6 participants) or placebo doses (7 participants) for 6 wk.
Outcome Measures: Self ratings.
  1. Mean average tolerated dose was 31 mg/day orally and 43 mg/day rectally delivered THC.
  2. Significant improvement in pain was seen on day one compared to baseline measures (p=0.047).
  3. No significant improvement in pain was seen compared to placebo on day 8 and 43.
  4. Individuals in the oral THC group showed no significant difference in mood or attention compared to the placebo group or to baseline.
  5. Total of 9 dropouts during open-label phases were due to increased pain, anxiety, decreased compliance, decreased attention and mood.

Discussion

Four randomized-controlled trials examined the effects of cannabinoids for pain in SCI; one study found that cannabinoids significantly reduced pain, two studies found no significant difference in pain reduction between cannabinoids and placebo and in the fourth study the RCT analysis of the primary outcome measure was not possible due to the high drop-out rate, the open-label part showed a significant reduction in pain.

Wilsey et al. (2016) found cannabis vapor significantly reduced pain post-SCI compared to placebo vapor. Rintala et al. (2010) examined the effect of dronabinol versus an active control (diphenhydramine) on neuropathic pain post-SCI in a small pilot RCT (n=5). They had two dropouts during the first phase of the study: one participant dropped out while on dronabinol due to side effects and the other participant on dronabinol did not want to stop medication for wash-out phase. The study found no significant difference in pain intensity between the two treatments in the 5 participants who completed the full trial. In addition to the small size of the RCT, limitations include the use of convenience sampling and use of two different baseline measures: the end of week 1 for phase 1 versus the end of wash-out for phase 2.

Hagenbach et al. (2007)conducted a study primarily examining the effectiveness of THC in improving spasticity and secondarily, in improving spastic pain in people with SCI. In the first phase of the study, 22 participants received 10mg of oral THC which was then dose titrated until maximum tolerance or treatment dose was reached for 6 weeks. The main analysis of the RCT part of the study was not possible due to the high dropout rate. In the open-label phase they found a significant reduction in pain of people with SCI post treatment (p=0.047). There was no significant reduction of pain compared to placebo on day 8 and 43 when comparing the intervention group of open-label part of the study to the placebo group in the RCT part of the study. Four patients noted pain relief (18%), but five (23%) reported pain augmentation and four dropped out: pain was one of the major reasons for the high dropout rate. We assign it a lower level of evidence (i.e., level 2) than would be expected of an RCT (i.e., PEDro≥6 RCT).

Andresen et al. (2016) did an RCT on the effects of the endocannabinoid palmitoylethanolamide (PEA), marketed in ultramicronized form as Normast. They administered it or a placebo twice a day with 12 hours between dosages for 12 weeks. Using a numeric rating scale from 0 to 10, they found no significant difference in neuropathic pain intensity between the two groups (p=0.46).

Conclusion

There is level 1b evidence (Wilsey et al. 2016) that natural cannabis vapour improves neuropathic pain post- SCI.

There is level 1b evidence (Andresen et al. 2016) that ultramicronized Palmitoylethanolamide (PEA/Normast) does not significantly improve chronic neuropathic pain post-SCI.

There is level 2 evidence (from one randomized-controlled crossover pilot trial: Rintala et al. 2010) that synthetic dronabinol may not be effective in reducing neuropathic pain intensity post SCI.

There is conflicting level 2 evidence (from one randomized controlled trial: Hagenbach et al. 2007) for the use of synthetic delta-9-tetra hydrocannabinol in reducing spastic pain in SCI individuals.

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