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Cannabinoids in Post-SCI Pain

Wade et al. (2003) note that delta-9-tetra hydrocannabinol (THC) and other cannabinoids have been shown to improve both tremor and spasticity in animal models of multiple sclerosis supported by anecdotal reports that cannabis relieves some of the troublesome symptoms of multiple sclerosis and spinal cord injury (Baker et al. 2000; Consroe et al. 1997; Dunn & Davis 1974; Martyn et al. 1995; Meinck et al. 1989; Petro & Ellenberger 1981; Ungerleider et al.1987). There is a clinical impression that marijuana smoking is very common among patients post-SCI; however, there are social and legal implication to its use and medical concerns about smoking as a delivery system.

Table 30 Cannabinoids and Post-SCI Pain

Author Year

Country

PEDro Score

Research Design

Total Sample Size

MethodsOutcome
Wilsey et al. 2016

USA

RCT Crossover

PEDro=8

N=42

Population: Mean age=46.4±13.6 yr; Gender: males=29, females=13; Level of injury: C=22, T=14, L=6; Severity of injury; Type of pain=neuropathic.

Intervention: Participants completed all conditions over the course of 3 8 hr sessions, during which were given either a placebo cannabis vapor, 2.9%, or 6.7% delta-9 THC with assessments taken at time of administration and hourly after for 7 hrs. Crossover design was used so each session they were given a different treatment condition.

Outcome Measures: Pain intensity numeric rating scale (NRS), pain relief (patient global impression of change (PGIC)), neuropathic pain scale (NPS), allodynia visual analog scale (VAS), heat-pain threshold, drug effect VAS, spasticity NRS and PGIC, modified Ashworth scale (MAS) for spasticity, vital signs (heart rate (HR), blood pressure (BP)), neurocognitive assessments (attention and concentration, fine motor speed processing speed and learning and memory (Wechsler adult intelligence scale digit symbol test (DST), (trail marking test (TMT), grooved pegboard test (GBT), paced auditory serial addition test (PASAT), Hopkins verbal learning test revised (HVLT)).

1.     Significant dose effect on pain intensity was observed after controlling for baseline pain (p<0.0001) and a significant stairstep effect between conditions was observed where significantly less pain was felt at the 2.9% delta 9-THC dose compared to baseline, and significantly less pain was felt at the 6.7% dose compared to baseline and the 2.7% dose.

2.     Pain intensity was observed to be significantly lower for both dosages of delta 9-THC compared to baseline (p<0.05), but only the 6.7% dose showed significance over the following 2 hrs (p<0.01).

3.     Four sided effects (“bad drug effect,” “nauseous,” “changes perceiving time,” and “difficulty remembering things”) showed no significant effect on pain, but others did (p ranged from <0.0001 to p=0.02), but main effect for delta 9-THC treatment remained significant above all effects of psychomimetic measures (p<0.0004).

4.     18 participants achieved a 30% pain reduction (clinically important while using placebo, while 26 and 35 reached 30% for the lower and higher dosages respectively.

5.     Significantly more pain relief with active cannabis compared to placebo (p<0.0001) and the effect was observed immediately after vaporization (p<0.005) and 1 hr (p<0.04), but not 2 hrs later (p>0.2).

6.     For second vaporization, but active cannabis doses provided greater pain relief than placebo immediately (p<0.001) and one hour later (p<0.05), but only one dose remained effective in reducing pain significantly compared to placebo (2.9% at time 360, p=0.03; 6.7% at time 420, p=0.03) with no time showing a significant difference in pain relief between active delta 9-THC doses.

7.     Across all timepoints, measurements of NPS showed that vaporized cannabis positively and significantly affected all measured multidimensional pain descriptors associated with neuropathic pain, even after controlling for baseline levels (p<0.0001 except for itching: p=0.04).

Andresen et al. 2016

Denmark

RCT

PEDro=

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 (Normast) group or a placebo group taking dosages 2 times daily with 12 h between dosages, for 12 wks.

Outcome Measures: Change in neuropathic pain intensity from baseline wk to wk 12 and 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 resuce 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).

Rintala et al. 2010

USA

RCT

PEDro=5

N=7

Population: Mean age: 50.1 yr. Severity of injury: AIS A=4, B=1, D=2. Level of injury: paraplegia=4, tetraplegia=3. Mean time since injury was 21.9 yr. Type of pain=neuropathic,

Treatment: Participants were randomized into two groups: 1) 5 mg dronabinol titrated every third day (max 20 mg/day) ; 2) 25 mg diphenhydramine day one then titrated up to 75 mg/day. Participants remained in a seven day stabilization phase once titration was complete and then a 28 day maintainence phase. Next participants completed a nine day weaning-off phase followed by a seven day washout period. Each participant then crossed over to the other group.

Outcome Measures: Brief Pain Inventory (BPI)

1.     Pain intensity was not significantly different between the dronabinol and diphenhydramine groups.

2.     No significant difference was seen in side effects between the groups.

3.     Most common side effects included dry mouth, constipation, fatigue and drowsiness.

 

Hagenbach et al. 2007

Switzerland

 

Phase 1-2

Non-RCT

N=25

 

Phase 3

RCT

PEDro=4

N=13

Population: SCI (N=15): Age=29-66 yr; Gender: males=11, females=2; Level of injury: C4-T11; Severity of injury: AIS: A,B,C,D Type of pain=neuropathic.

Treatment: Phase 1-2: Patients received 10 mg oral tetra hydrocannabinol (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 manner, 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 weeks.

Pain Scale: Self ratings

1.     Significant improvement in pain was seen on day one compared to baseline measures (p=0.047).

2.     No significant improvement in pain post SCI was seen compared to placebo on day 8 and 43.

3.     Individuals in the oral THC group showed no significant difference in mood or attention compared to the placebo group or to baseline.

 

Discussion

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 pain post SCI. The study found no significant difference on pain intensity between the two treatments.

Hagenbach et al. (2007) conducted a study examining primarily the effectiveness of THC in improving spasticity and secondarily, in improving pain with SCI individuals. In the first phase of the study, 22 individuals received 10mg of oral THC which was then dose titrated until maximum tolerance or treatment dose was reached for 6 weeks. The study found a significant reduction in the pain of SCI individuals post treatment (p=0.047). The third phase of the study involved a double blind randomized control trial which included 13 of the previously mentioned individuals receiving either individual maximum treatment dosage previously determined or a placebo dose. In this phase, Hagenbach et al. (2007) found individuals in the treatment group had no significant pain reduction compared to those in the placebo group.

Given that marijuana has anecdotally been thought to have benefits for post-SCI pain, Wade et al. (2003) conducted an RCT of sublingual 2.5 mg THC and/or cannabidiol and found that it helped to reduce pain, muscle spasm, spasticity and sleep in a group of largely multiple sclerosis patients with neuropathic pain. It is of note that only a small percentage of the patients in this study had spinal cord injuries hence did not meet inclusion criteria. Cannabinoids are a promising treatment, which would benefit from other studies.

Conclusion

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

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

There is level 2 evidence (from one randomized controlled trial; Rintala et al. 2010) that dronabinol is not effective in reducing pain intensity post SCI.

Cannabinoids are a potential new treatment for post-SCI pain in need of further study.

Dronabinal is not effective in reducing pain post SCI.