* Change in the primary analysis variable from the 30% responder analysis to the continuous responder analysis with resulting increase in sample size from 370 to 380 participants. * Removal of Quality of Life assessments from the protocol as they were not sensitive enough to detect a difference between Sativex and placebo but did add excessive burden to participants. These were replaced with 2 simple questions asked to participants at each study visit about a) their level of constipation and b) their satisfaction with their medicine and recorded on a simple 0-10 NRS scale. * Reinforcing the point that the protocol included a study population which was one of terminally ill, advanced cancer patients and that Sativex was to be dosed twice-daily, not as-needed. * The dosing paradigm was described more specifically. * The definition of optimized therapy was improved and a minimum threshold level of morphine equivalence (>90 mg transdermal drug delivery) was added for those participants where it was deemed clinically inappropriate to increase their dose because no further efficacy benefit was expected. * How rescue analgesia was addressed in the statistical analysis was clarified. * Various updates to bring in line with the current protocol template, internal safety operating procedures, and any updated legislation. * The PGIC questionnaire was updated. * Safety follow-up period extended to 2 weeks.

* Wording in Section 4.1.1 was amended to make it clearer for the reader with regards to the length of the eligibility period, changes to opioids during this period, and potential rescreening of participants. * The protocol was also updated to reflect an amended and expanded non-linear ‘morphine equivalence’ conversion scheme for methadone doses. * Wording where needed was amended to clarify that regular around the clock dosing with immediate-release opioids as a maintenance dose, was ideally to be every 4 hours. * Section 8.6, Access to Blinded Treatment Assignment, was updated to clarify to investigators that it was acceptable to unblind prior to contacting GW, but where possible, GW encouraged communication first. * The wording in Section 9.1.8, Clinical Laboratory Sampling, was revised to clarify how the THC test at Screening was performed and that there was a secondary test to confirm any initial positive THC tests. * Section 11.7, Follow up Procedures for Adverse Events, was updated following Food and Drug Administration guidance to clarify that GW may have needed to follow up with the center on certain adverse events of special medical interest, in particular those associated with abuse potential or addiction.

* An annex to the protocol was issued to describe the methodology for identifying and evaluating clinical study adverse event data through systematic categorization, tabulation, and analysis that can illuminate an abuse potential signal. This impacted study procedures for United States and United Kingdom centers from the point of implementation onwards.