Table 1.

Interventional Clinical Studies for Tapentadol That Have Completed Phase 4

#	Study Title	Study Arms	Intervention/Treatment	Conditions	Primary Outcome Measures	Publications Resulted from the Study
1	Comparison of Increasing Doses of Tapentadol Versus A Combination of Tapentadol and Pregabalin	Experimental: Tapentadol Prolonged Release Tapentadol Prolonged Release (100–500 mg per day) Oral administration twice daily	Drug: Tapentadol Prolonged Release 100–500 mg per day orally twice daily for a maximum of 12 weeks	Low Back Pain Neuropathic Pain	Change in the Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3) [Time Frame: Randomization (Day 22); Final Evaluation Visit (Day 77)] The primary endpoint is defined as the comparison of tapentadol prolonged release (PR) 300 mg plus 200 mg per day and the combination of tapentadol PR 300 mg per day and pregabalin 300 mg per day regarding the change in NRS-3 pain intensity scores (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) from the randomization visit to the final evaluation visit. Theoretically a maximum decrease of −10 and an increase of +4 in the pain intensity would have been possible. A negative sign indicates a decrease in pain intensity from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline visit)	[37,38]
			Drug: Tapentadol Prolonged Release open label maintenance 100–400 mg per day Tapentadol Prolonged Release orally administered twice daily
		Active Comparator: Tapentadol Prolonged Release with Pregabalin Tapentadol Prolonged Release (100–300 mg per day) with Pregabalin (150–300 mg per day) Both administered orally twice a day	Drug: Tapentadol Prolonged Release with Pregabalin Tapentadol Prolonged Release 100–300 mg per day with Pregabalin 150–300 mg per day orally twice daily for a maximum of 12 weeks
			Drug: Tapentadol Prolonged Release open label maintenance 100–400 mg per day Tapentadol Prolonged Release orally administered twice daily
2	Comparison of the Effects of Tapentadol and Oxycodone on Gastrointestinal and Colonic Transit in Humans	Active Comparator: Tapentadol (75 mg tapentadol tid)	Drug: Tapentadol Subjects received tapentadol immediate release formulation, 75 mg three times per day (tid) for 48 hours. Other Name: Tapentadol brand name: Nucynta	Effects of 2 Mu-opiates on Gastrointestinal Transit	1. Colonic Transit, Geometric Center at 24 Hours [Time Frame: 24 hours] The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. 2. Gastric Emptying Half-time (t1/2) at 24 Hours [Time Frame: 24 hours]	NON
		Active Comparator: Oxycodone (5 mg oxycodone tid)	Drug: Oxycodone Subjects received oxycodone immediate release formulation, 5 mg three times per day (tid) for 48 hours. Other Names: Dazidox ETH-Oxydose Endocodone Oxecta Oxy IR Oxycontin Oxyfast Percolone Roxicodone
		Placebo Comparator: Placebo Placebo tid	Drug: Placebo Subjects received placebo three times per day (tid) for 48 hours.
3	Tapentadol Prolonged Release (PR) Versus Oxycodone/Naloxone Prolonged Release in Severe Chronic Low Back Pain With a Neuropathic Component	Experimental: Tapentadol Prolonged Release (PR)	Drug: Tapentadol Prolonged Release All participants started with 50 mg tapentadol hydrochloride prolonged release (twice daily). The dose of tapentadol hydrochloride prolonged release will be adjusted in increments of 50 mg to a level that provided adequate analgesia. Titration will be after a minimum of 3 days on a dose. Participants are permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants will remain on the stable dose for 9 weeks.	Back Pain Low Back Pain Neuropathic Pain	1. Change in the Average Pain Intensity Score on an 11-point Numeric Rating Scale (NRS-3) [Time Frame: Baseline (Randomization Visit); End of Continuation Period (Week 12)] For this pain assessment, the participant indicated the level of average pain experienced over the previous 3 days on an 11-point Numeric Rating Scale (NRS-3) where a score of 0 indicated “no pain” and a score of 10 indicated “pain as bad as you can imagine”. The value reported represents the change from the randomization visit (ie, the last 3 days in the washout period prior to Investigational Medicinal Product initiation and titration) to the end of the continuation period (ie, up to 9 weeks on the stable dose). The theoretical values range from −10 to 10. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline Visit). 2. Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) Total Score [Time Frame: Baseline (Randomization Visit); End of Continuation Period (Week 12)] The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assessed the severity of symptoms of constipation. Participants were asked “How severe have each of these symptoms been in the last two weeks?” eg “Pain in your stomach”. There are 3 subscales: 4 questions on abdominal symptoms, 3 on rectal symptoms and 5 on stool symptoms. Responses were rated on a 5-point Likert scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation. The change in the assessment of constipation symptoms (PAC-SYM) total score from the Randomization Visit to the Final Evaluation Visit. The PAC-SYM overall score is the sum of scores of all non-missing items divided by the number of non-missing items (if at least 6 items were non-missing).	[39]
		Active Comparator: Oxycodone/Naloxone Prolonged Release	Drug: Oxycodone/Naloxone Prolonged Release All participants start with 10 mg/5 mg oxycodone/naloxone (twice daily). The dose of oxycodone/naloxone may be adjusted in increments of 10mg/ 5 mg oxycodone/naloxone to a level that provide adequate analgesia. Titration will be after a minimum of 3 days on a dose. Participants will be permitted a maximum dose of 50 mg/ 20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants will remain on the stable dose for 9 weeks.