## 3 Human Studies
### Cannabinoids May Be Effective in Reducing Neuropathatic Pain in pwMS  
Neuropathatic pain (NP) is thought to be caused by a lesion in, or dysfunction of the CNS, possibly as a result of corticospinal system disinhibition or chronic activation of nociceptive afferents, and is a common symptom of MS affecting between 17% and 70% of patients [47; 48]. In a study by [PERSON] et al., 28 pwMS were recruited for a two-phase study [73]. These patients were administered Sativex for one month. This study aimed to examine the possibility of Sativex reducing pain, which was quantified by NRS scores, laser evoked potentials were also used to detect subcortical lesions. Seventy four percent of patients responded to Sativex at the end of phase A, but there was no significant difference between pain NRS scores and laser evoked potential amplitude between Sativex treatment group and baseline scores. The results of phase B showed that Sativex was effective in relieving pain NRS scores and caused a reduction in amplitude in laser evoked potentials. The results of this study suggest that Sativex is an effective method of reducing NP in pwMS, despite this, it should be noted that this study did not implement a placebo group and the observation period was relatively short. A more favourable study design was implemented by [PERSON] et al., who implemented a double-blind placebo-controlled parallel-group design in a large sample size of 393 patients [74]. In phase A of this study, the double-blind placebo group, patients were given either Sativex or a control substance. Each 100 \(\mu\)L activation of the spray delivered 2.7 mg of \(\Delta^{9}\)-THC and 2.5 mg of CBD to the oral mucosa. Patients were restricted to a maximum of 12 sprays a day. In phase A, those receiving Sativex self-administered a mean of 8.8 sprays a day compared to a mean of 11.1 in the placebo group. Fifty percent of patients in the Sativex group displayed a 30% reduction in pain NRS scores, whereas 45% of patients in the control group displayed a similar reduction. At the end of this phase, patients in the treatment group had a mean pain NRS reduction of 1.93 points, and patients in the control group had a mean reduction of 1.76 points. Similarly, none of the secondary endpoints of this study (Brief Pain Inventory - Short Form, Subject Global Impression of Change) and sleep quality assessments displayed a statistically significant difference in favour of the treatment. These results did not reach statistical significance, but, were clinically relevant. At the end of phase B of this study, the open-label phase, only 24% of patients failed treatment with Sativex compared to 57% in placebo, suggesting the efficacy of primary endpoints (NRS scores) and some secondary endpoints. In another study, [PERSON] et al. also studied the effects of Sativex in 10 pwMS with NP and 10 pwMS without NP [79]. These researchers evaluated the drug effects on a pain NRS, MAS and by neurophysiological measures. During treatment, all patients were taking anti-convulsant drugs (most commonly baclofen), 40% of these patients occasionally took analgesics for pain relief. After one month of drug administration, pwMS with NP showed significant reductions in pain NRS scores and showed improved scores on measures of quality of life. These effects were salient with the neurophysiological findings which showed an increase of frontocentral \(\gamma\)-band oscillation and pain motor integration strength. The data from this study supports the effectiveness of Sativex in pain relief in NP pwMS and improved quality of life. These authors suggest that Sativex may also boost cortical pain gating mechanisms as clinical pain relief was salient with the findings of activation of sensory-motor areas supporting the idea that Sativex may restore cortical pain gating mechanisms, most likely through modulation of sensory-motor integration concerning painful stimulation [37; 55]. A 2005 study by [PERSON] et al. studied the effects of nabiximab on central NP in a randomised control trial [80].