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Cannabinoids for Reducing Spasticity after SCI

The medicinal and psychoactive properties of cannabinoids have been recognized for an estimated 5000-8000 years (Mechoulam 1986; Reynolds 1890). There are 60 raw cannabinoids identified but only six are pharmacologically active. Delta 9 tetra-hydrocannabinol (THC) is the main psycho-active ingredient and it is now available in prescribable synthetic (dronabinol, nabilone) and plant derived forms. Human cannabinoid receptors (CB1 and CB2) were discovered in the 1980s and 1990s (Howlett et al. 1986; Devane et al. 1988; Kiminski et al. 1992) along with these receptors, naturally occurring cannabinoid like substances (endocannabinoids) have been discovered in animals and humans. Baker (2001) showed that administration of CB1 agonists in an animal model for MS led to reduction in spasticity and tremor. In the same study the administration of CB1 antagonists not only reversed the effect of the agonist but made symptoms of spasticity and tremor worse. Since 2005, there has been an average of 20 new publications per week on the medical uses of cannabis. However, there is a paucity of literature on the use of cannabinoids specifically for the management of spasticity in SCI.

In the central nervous system cannabinoids have been shown to decrease the release of excitatory neurotransmitters, like glutamic acid, from presynaptic nerve terminals. They have also been shown to modulate calcium channels (Pertwee 2002) and enhance GABA function in the brain (Musty & Consore 2002). These are all possible mechanisms of spasticity reduction.

Table 26 Delta-9-tetrahydrocannacinol for Reducing Spasticity

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
Nabilone
Pooyania et al. 2010

Canada

RCT Crossover

PEDro=8

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 or placebo during the first 4 wk period (0.5 mg 1x/day with option to increase to 0.5 mg 2x/ day); after a 2 wk washout, subjects were crossed over to opposite arm.

Outcome Measures: Ashworth Scale (AS), Spasm Frequency Scale (SFS), Visual Analog Scale (VAS), Wartenberg Pendulum Test, Global Impression of Change.

1.      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).

2.      There was no significant difference in other measures.

3.      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.

Detra-9-tetrahydrocannabinol (dronabinol)
Hagenbach et al. 2007

Switzerland

Phase 1–Pre-Post

Phase 2–RCT

PEDro=6

N=22 (RCT N=15)

Population: Age range: 29-66 yr; 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 labell oral and rectal detra-9-tetrahydrocannabinol (dronabinol). Phase 2- Oral detra-9-tetrahydrocannabinol (dronabinol) versus placebo.

Outcome measures: Modified Ashworth Scale (MAS), Self rating of spasticity and side effects.

 

 

1.     Main comparison of RCT (dronabinol versus placebo) was not analyzed due to potential confounds associated with large group differences on SSS.

2.     For the Phase I pre-post comparison of dronabinol, mean SSS decreased significantly during active treatment compared to control on day one (p=0.001), day 8 (p=0.001) and day 43 (p=0.05) of treatment.

3.     When comparing dronabinol versus placebo (Phase 1 versus Phase 3), 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).

4.     When comparing dronabinol versus placebo (Phase 1 versus Phase 3) there was a significant decrease in self-rated spasticity on day 1 (p=0.033) but not for days 8 or 43 (p>0.05).

5.     There were no significant differences on mood or psychological testing in intervention versus placebo groups.

6.     There was no significant increase on FIM scores, but one tetraplegic individual was able to perform CIC independently after intervention due to better motor control of the hands.

7.     Drop outs 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.

Maurer et al. 1990

Switzerland

Single Subject RCT

PEDro=3

N=1

Population: Gender: males=1, females=0; Injury etiology: SCI=1.

Intervention: 50 mg of codeine, 5 mg of detra-9-tetrahydrocannabinol (dronabinol) or placebo, randomized using an ABC design in multiple trials.

Outcome Measures: Visual Analog Scale (VAS) for spasticity, pain, sleep, micturition, ability to concentrate and mood. Rating occurred next day after intervention administered (2130 hr nightly) and with respect to spasticity asked about immediate effect, effect while falling asleep, effect during the night and effect in the morning after intervention.

1.      Delta 9 THC demonstrated a significant decrease in all of the VAS ratings for spasticity compared to codeine and placebo.

2.      Delta 9 THC also showed a significant reduction in pain compared to placebo.

Kogel et al. 1995

USA

Pre-Post

N=5

Population: Age range: 28-55 yr; Gender: males=5, females=0; Level of injury: tetraplegia; Time since injury range: 6 mo–9 yr.

Intervention: Open label design: Oral detra-9-tetrahydrocannabinol (dronabinol) (initial dose: 5 mg bid, increased to 20 mg tid)+current spasticity regimen.

Outcome Measures: Pendulum Drop Test, Weschler Memory Scale (WMS), Profile of Moods Scales (POMS).

1.     Spasticity was markedly improved in 2 of 5 subjects.

2.     Results fluctuated in one subject, did not change in one subject and worsened in one subject.

3.     There was no worsening in psychological parameters and two subjects had improvements in memory testing.

All Types
Malec et al. 1982

USA

Observational

N=43

Population: Age range: <20-60+ yr; Gender: males=37, 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/nonuse, Spasticity Change Index, computed by subtracting level of spasticity in the drug-state from the non-drug-state.

1.     SCI persons reported decreased spasticity with marijuana use; present use of marijuana correlated positively with past use.

2.     The person’s reference or peer group contributed significantly to current use. 53% reported using marijuana during last yr 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).

3.     Reduction in spasticity via use was reported in 88% (21/24) while 12% reported no change.

4.     No correlation between Spasticity Change Index and any variable (if significant correlation, then perhaps placebo effect).

5.     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 prevalent (53%, 23/43) among SCI surveyed and especially of SCI <30 yr (76%, 16/21).

Discussion

There continues to be a paucity of literature on the use of cannabinoids for the management of spasticity in SCI. They are often described in cases with intractable spasticity in patients who have not responded to standard treatments which may bias studies in favor of a negative outcome. In addition to a single subject, blinded, controlled study (Maurer et al. 1990) there have been only two placebo-controlled trials (Hagenbach et al. 2007; Pooyania et al. 2010) and the remainder of the literature is limited to pre-post and observational study designs.

Hagenbach (2007) performed a trial consisting of two open label phases followed by a double-blind, randomized, placebo control phase in order to evaluate the efficacy and side effects of orally and rectally delivered delta 9 THC (dronabinol) for the treatment of SCI related spasticity. The main outcomes were the spasticity sum score (SSS) using the MAS as well as self-rating of spasticity. In the open label phase, significant reductions in spasticity were seen in both oral and rectal THC groups. Only oral administration was used in the placebo control phase. When comparing phase one to phase three results, mean SSS decreased significantly during active treatment compared to placebo on day one (p=0.001), day eight (p=0.001) and day 43 (p=0.05) of treatment. There was a significant subjective decrease in spasticity on day one (p=0.033) but not day eight or 43. There were no significant differences found with the remaining outcome measures. Unfortunately, there were numerous dropouts within the first two phases due to increased pain, anxiety, decreased compliance, decreased attention and mood. This likely contributed to large between group differences for the baseline spasticity scores and led to a decision to abandon analysis of the active compound-placebo comparison. Therefore, despite the various findings noted above which demonstrated reduced spasticity with delta nine THC, it remains unclear if placebo effects may have contributed to these findings as there was an indication of placebo effects within the comparison of open label and placebo-control results. Given the limitations associated with this study (i.e., lack of analysis of placebo-treatment analysis) it was assigned a lower level of evidence (i.e., level 2) even though it achieved a PEDro score consistent with an assignment of level 1 (i.e., PEDro≥6) according to SCIRE criteria.

The second study was a double-blind placebo-controlled crossover (Pooyania et al. 2010) which gave patients Nabilone or a placebo during the first four weeks, 0.5 mg/ day with some increasing to twice a day. Following a two-week washout, the subjects were crossed over to the opposite arm. The main finding was a significant decrease in spasticity for those on active treatment in involved (p=0.003) and overall muscles (p=0.001). Similarly, to the previous study, the other outcome measures rendered no significant differences. However, the two trials differed in reported side effects as this second study documented only mild and tolerable side effects.

Maurer et al. (1990) studied one patient with pain and spasticity due to SCI. Despite not meeting the SCIRE inclusion criteria, it was included due to the paucity of literature pertaining to cannabinoids for the management of spasticity in SCI, and because it was a randomized ABC (three period, three treatment crossover) design. Using a visual analog scale to assess spasticity after blinded treatment, delta 9 THC showed significant benefits for spasticity over placebo and codeine. However, the patient was exposed to THC use prior to the placebo control trial which may have introduced significant bias.

Kogel et al. (1995) performed a pre-post trial in five males with paraplegia. He administered dronabinol escalating from five mg BID to 10 mg QID to 20 mg TID. The main outcome was the pendulum test and secondary outcomes were the Weshler memory test and profile of mood states. Two of the five subjects had marked improvements in their spasticity. One showed fluctuating responses, one no change and one worsened. The psychological testing was only performed on four of the five subjects but no deleterious effects were noted and in fact two subjects improved on memory testing.

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 2 evidence (from one compromised RCT; Hagenbach et al. 2007 and 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 has 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.