Cannabinoids in SCI

Spasticity

Table 2. Spasticity, Cannabinoids and SCI

Author Year; Country Research Design Score Total Sample Size	Methods	Outcome
Nabilone
Pooyania et al. 2010; Canada RCT Crossover PEDro = 8 Level 1 N = 11	Population: Mean age: 42.4 yr: Gender: males=11, females=0; Injury etiology: traumatic, non-traumatic SCI; Level of injury: tetraplegia=6, paraplegia=5; Time since injury: >1yr. Intervention: Individuals received either nabilone in tablet form or placebo during 4 wk. period (0.5-1.0 mg/day) with crossover design with 2 wk. wash-out period in between. Outcome Measures: Ashworth Scale (AS), Spasm Frequency Scale (SFS), Visual Analog Scale (VAS), Wartenberg Pendulum Test, Global Impression of Change.	A significant decrease in SFS, as measured by the AS, was observed for those on active treatment in the most involved muscle (mean difference=0.909±0.85; p=0.003), as well as for muscles overall (p=0.001). There was no significant difference in other measures. Side effects were mild and tolerable.
	Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data
Tetra-9-tetrahydrocannabinol (dronabinol)
Hagenbach et al. 2007; Switzerland Phase 1–Pre-post Level 4 Phase 2–RCT PEDro = 6 Level 1 N = 22 (RCT N = 13)	Population: Age range: 29-66 yrs; Gender: males=11, females=2; Injury etiology: SCI=15; Level of injury: C4-T11; Level of severity: AIS: A, B, C, D. Intervention: Phase 1–Open label oral and rectal detra-9-tetrahydrocannabinol (dronabinol). Phase 2- Oral detra-9-tetrahydrocannabinol (dronabinol) versus placebo. Outcome measures: Spasticity Sum Score (SSS) (average of 2 x independent left/Right Modified Ashworth Scale (MAS) scores of 6 joints), Self-rating of spasticity and side effects.	Phase 2 (RCT): main comparison (dronabinol versus placebo) was not analyzed due to potential confounds associated with large baseline group differences on SSS. Phase 1 (pre-post dronabinol/rectal THC): mean SSS decreased significantly during active treatment compared to control on day one (p<0.001/p<0.05), day 8 (p<0.001/P<0.05) and day 43 (p<0.05/p<0.05) of treatment. Phase 1 vs 2: (open label dronabinol versus placebo): Mean SSS decreased significantly relative to placebo over days 1, 8 and 43 by a mean of 4.89 as compared to baseline (p=0.001). Significant decrease in self-rated spasticity on day 1 (p=0.033) but not for days 8 or 43 (p>0.05). No significant differences on mood or psychological testing, nor on FIM scores in intervention versus placebo groups. Total of 9 dropouts during open-label phases were due to increased pain, anxiety, decreased compliance, decreased attention and mood.
	Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data
Wilsey et al. 2016; USA RCT Crossover PEDro = 8 Level 1 N = 42 (29 SCI)	Population: Mean age=46.4±13.6 yrs; 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: Numeric Rating Scale of Spasticity (NRSS) for spasms, pain and muscle stiffness & Patient Global Impression of Change (PGIC)	9% THC group: spasticity was significantly reduced at t = 420 min. (p<0.0001) and patients experienced pain relief at t = 420 (p=0.0227). No significant results at other measure points. 6.7% THC group: no significant change in spasticity
Kogel et al. 1995; USA Pre-Post Level 4 N = 5	Population: Age range: 28-55 yrs; Gender: males=5, females=0; Level of injury: tetraplegia; Time since injury range: 6 mos–9 yrs. Intervention: Open label design: Oral detra-9-tetrahydrocannabinol (dronabinol), with dose escalation: 2x5mg/day – 4×10 mg/day – 3x20mg/day) + current spasticity regimen. Outcome Measures: Pendulum Drop Test, Weschler Memory Scale (WMS), Profile of Moods Scales (POMS).	Spasticity was markedly improved in 2 of 5 subjects. Results fluctuated in one participant, did not change in one participant, and worsened in another participant. Psychological testing was unchanged (n = 4), with 2 improving on memory testing
Non-Specified Types
Malec et al. 1982; USA Observational Level 5 N = 43	Population: Age range: <20-60+ yrs; Gender: males=38, females=5; Injury etiology: 43; Time since injury range: 6 mo-5+ yr. Intervention: Survey to examine the perceived effects of cannabis on spasticity. Outcome Measures: Customized cross-sectional survey addressing demographic information (age range, sex, marital status, education, and range of time since injury), marijuana use, belief patterns associated with use, severity of spasticity associated with use/non-use, Spasticity Change Index, computed by subtracting level of spasticity in the drug-state from the non-drug-state.	SCI persons reported decreased spasticity with marijuana use; present use of marijuana correlated positively with past use. The person’s reference or peer group contributed significantly to current use. 53% reported using marijuana during last year with correlation to use prior to SCI (r=0.78, p<0.001, n=43; agrees with other studies). Also correlated with degree of use in present social reference group (r=0.32, p<0.05, n=38) and prior social reference group (r=0.30, p<0.05, n=37). Age was negatively correlated with current use (r=-0.56, p<0.001, n=43). Reduction in spasticity via use was reported in 88% (21/24) while 12% reported no change. No correlation between Spasticity Change Index and any variable (if significant correlation, then perhaps placebo effect). Education moderately correlated with reported change in spasticity (r=-0.65, p<0.001, n=23): lower education associated with greater reported change in Spasticity Change Index. Marijuana use prevalence (53%, 23/43) among SCI surveyed and especially of SCI <30 yr (76%, 16/21).

Discussion

Hagenbach et al. (2007) performed a trial consisting of two open label phases; (I) dronabinol (oral THC) and (II) rectally delivered THC (followed by (III) double-blind, randomized, placebo control phase of oral dronabinol to evaluate efficacy and side effects for the treatment of SCI related spasticity. The main outcomes were the spasticity sum score (SSS) using the Modified Ashworth Scale as well as self-rating of spasticity. Due to numerous dropouts within the open label phases, the baseline SSS between groups were too large to perform the main analysis of phase III (dronabinol vs. placebo). In the open label phase, significant reductions in spasticity were seen in both oral and rectal THC groups. Analysis of dronabinol (phase I) versus placebo (phase III) was done instead: mean SSS decreased significantly on day 1 (p=0.001), day 8 (p=0.001) and day 43 (p=0.05). Self-rated spasticity decreased significantly on day 1 (p=0.033) but not day 8 or 43. There were no significant differences found with the remaining outcome measures. Due to the limitations in analysis, it remains unclear if placebo effects may have contributed to the positive findings in this study. We assign it a lower level of evidence (i.e., level 2) than would be expected of an RCT (i.e., PEDro≥6 = Level 1 RCT).

Pooyania et al. (2010) performed a double-blind, placebo-controlled, crossover trial of nabilone (0.5-1.0 mg/day) vs. placebo for 4 weeks for each treatment period with a 2-week washout period in between. They found a significant decrease in spasticity for those on active treatment (p=0.003) and overall muscles (p=0.001). There were no significant differences in other outcome measures. Contrary to Hagenbach et al. (2007), they reported only mild and tolerable side effects in this trial.

Wilsey et al. (2016) performed a crossover trial of placebo, 2.9% and 6.7% THC with a treatment time of 480 min. Participants took 4 puffs at t = 0 and 4 puffs at t = 240 min. They found a significant reduction of spasticity measured on a spasticity severity scale for 2.9% THC at t = 420 min. (p<0.0001) with significant spasticity relief (p=0.0277) but found no significant differences for the 6.7% THC group at any measurement points.

Kogel et al. (1995) performed a pre-post trial of dronabinol with dose escalation (2x5mg/day – 4×10 mg/day – 3x20mg/day) in five males with paraplegia. Two participants showed significant improvement in the pendulum test for spasticity, 1 showed fluctuating responses, 1 had no change and 1 had worsened.

Conclusion

There is level 1b evidence (from one RCT: Pooyania et al. 2010) that nabilone is effective in reducing spasticity in both the involved and overall muscles.

There is level 1b evidence (from one RCT: Wilsey et al. 2016) that 2.9% THC vapour is effective in reducing spasticity measured on a spasticity severity scale 420 min after 4 inhalations and 180 min after 4 additional inhalations.

There is level 2 evidence (from one compromised RCT: Hagenbach et al. 2007; supported by one pre-post study: Kogel et al. 1995) to support the use of oral delta-9-tetrahydrocannabinol (dronabinol) in reducing both objective and subjective measures of spasticity.

Nabilone in tablet form and 2.9 % THC vaporized have been shown to be effective in reducing spasticity, but additional research is needed.

Oral detra-9-tetrahydrocannabinol (dronabinol) may help to reduce spasticity but requires additional evidence from controlled studies.