●Screening period extended to 14 days since the urine drug test might require 7 days. ●The Food and Drug Administration (FDA) recommended analgesic medications to be thoroughly documented after study drug discontinuation, including: ◌Subjects asked to record daily in a separate diary the intake of analgesic medications and study site collection of diary. ●Inclusion of conversion ratios of Tapentadol to morphine and Buprenorphine (Butrans®) to morphine (approved by FDA in 2008 and 2010, respectively) in the conversion table in the protocol. ●Use of 'prokinetic drug' not permitted in this study. ●More diary recordings (modified Subjective Opiate Withdrawal Scale [SOWS] before visit 5, rescue medication for constipation) at the time of study drug discontinuation. ◌Bowel function measures to be recorded at time of study drug discontinuation (SDD). ◌Modified SOWS always recorded in the diary daily from visit 3 until visit 5 during the double-blind period.

●FDA recommended the eligibility criteria be modified by standardizing the definition and diagnoses of OIC rather than OIC criteria being defined by the investigator. ●Efficacy variables and statistical methods were adjusted based on FDA comments on the protocol. ●Screening period was extended to 21 days since urine drug confirmatory test could require 10 business days. ●Due to scheduling issues, the language for open-label titration (OLT) period was updated to reflect 'up to 28 days for qualification' and 'up to 31 days for visit 3 for scheduling purpose'. ●Electrocardiogram (ECG) criteria for study (or study drug) discontinuation were modified based on other sponsor programs. ●Instructions to clarify the procedures when 2 visits (unscheduled SDD visit and a regularly scheduled visit, or unscheduled SDD follow-up visit and a regularly scheduled visit) coincided. ●Based on recruitment, the number of study centers was increased.

●Additional items were included in the electronic diary assessing bowel function. This was in order to capture relevant gastrointestinal (GI) symptoms using a validated scale and to ensure GI symptoms were captured on a daily basis. ●Subjects were allowed to take OxyIR® up to 2 pills daily (rather than 1 pill up to 2 times, at least 4 hours apart) during the double-blind period. This matched the use of OxyIR® during the 7 days of the OLT period used to qualify the subject. ●Two exclusion criteria related to nerve/plexus blocks were changed, neuroablation and neurosurgical procedures for pain control. ●The primary analysis for “average pain over the last 24 hours” variable was changed from a pattern mixture model including the use of data from retrieved dropouts to the same analysis without using data from retrieved dropouts. The rationale for the change was to address FDA concerns regarding the use of retrieved dropout data. ●Pharmacogenomic sampling was changed.

●To enhance enrollment, low back pain criteria was changed (low back pain with radiation below the knee was now allowed) and rescreening was allowed with medical monitor approval. ●Clarified exclusion criterion regarding neuropathic pain conditions. ●Clarified restrictions for nerve stimulators and intraspinal pain pumps. ●To enhance enrollment and facilitate entry into the double-blind period, OIC entry criteria was changed and the primary OIC variable was changed correspondingly. ●To facilitate entry into the double-blind period, the double-blind entry criterion requiring number of consecutive days of a stable dose of OXY was changed from 9 to 7. ●To accommodate time required to confirm positive urine drug tests at screening, the screening period was extended from 21 days to 28 days. ●Additional categories of medically qualified individuals were allowed to perform physical examinations. ●The time between replicate ECG measurements was reduced from 10 minutes to 5 minutes.

●Due to slow subject recruitment and a change in sponsor rationale for planning sample size for the overall CSBM responder rate, the following changes were made: ◌Sample of 200 subjects per treatment arm was thought to be sufficient for assessment of CSBM responder rate, but an interim analysis was deemed necessary in order to know whether the sample size needed adjustment, and ◌Since 200 subjects per treatment arm were not thought to be sufficient for assessment of analgesia, the previously specified primary and secondary analgesia endpoints were specified as other endpoints for the study and a pooled analysis of the data from trials ONU3704 and ONU3705 was planned for the analgesia efficacy endpoints. ◌Study objective on analgesic efficacy was changed from a primary objective to a secondary objective. ◌Analgesic efficacy variable, “average pain over the last 24 hours”, was changed from a primary efficacy variable to other efficacy variable. ◌Analgesic efficacy variables, Medical Outcomes Study-Sleep Scale, and Patient Global Impression of Change were changed from secondary efficacy variables to other efficacy variables. ◌Analysis for the primary and secondary efficacy variables were adjusted accordingly. ●To enhance enrollment, investigator centers were increased from 150 sites to 200 sites.