Summary of Patient Input

Six patient groups, The Chronic Pain Association of Canada, The Canadian Arthritis Patient Alliance, Arthritis Consumer Experts, The Halton/Hamilton Chronic Pain Support Group, Action Atlantic Pain Society, and the Chronic Pain Support Group of Sarnia-Lambton community in Ontario provided input for this submission. Patient perspectives were obtained through a call for patient input, interactions with patients suffering from pain (monthly meetings, survey, or emails), communications with professionals, discussions with scientific members of the patient groups, relationships with other patient groups, and ongoing research. The following is a summary of key input from the perspective of the patient groups:

• Pain has negative impacts on almost all aspects of day-to-day life, such as family relationships, social outings, workplace settings, and the ability to carry out daily activities. Patients’ quality of life (QoL) is greatly impaired by pain and patients may feel depressed, isolated, and helpless. Consequences of the negative impacts of pain include the inability to find gainful employment or the need to retire earlier than expected, which both also have financial implications.
• Many patients taking medications to treat their pain experience side effects of the drugs, most commonly constipation.
• Patients have difficulty accessing non-pharmaceutical treatments, such as physiotherapy and psychological treatment, in the public system, with significant costs associated with accessing such treatments privately.
• Medical training on pain management is very limited in Canada and it is a challenge to find a doctor who will treat pain. In most cases, patients have to wait 18 to 24 months to see a pain specialist.
• Based on input from one of the patient groups, it was felt that there are insufficient treatments for chronic pain, and that pharmaceutical options have the potential for serious risks and side effects that are often difficult to manage.
• In general, patients expect to see safer and more effective treatments for pain relief. They want new treatments that can relieve pain and improve function, are non-addictive and won’t cause withdrawal, have long-lasting effects, have fewer side effects, and can improve their QoL.
• Some patients who had experience with Nucynta reported an overall improvement in their QoL, including finding fewer side effects with Nucynta than with other medications, including non-opioid drugs.

Clinical Trials

The systematic review included five RCTs of patients with chronic non-cancer pain and three RCTs of patients with cancer-related pain:

• Three 15-week, double-blind (DB) RCTs in patients with knee osteoarthritis (Study PAI-3008, N = 1,030; Study PAI-3009, N = 990) or non-malignant low back pain (Study PAI-3011, N = 981) randomized (1:1:1) to one of placebo, tapentadol ER (100 mg to 250 mg twice daily), or oxycodone CR (20 mg to 50 mg twice daily). The proportions of patients who discontinued the study in the tapentadol ER group versus the oxycodone CR group were 47% versus 65% in Study PAI-3008, 44% versus 64% in Study PAI-3009, and 48% versus 59% in Study PAI-3011.
• One one-year, open-label (OL) RCT (Study PAI-3007, N = 1,121) in patients with knee or hip osteoarthritis or non-malignant low back pain randomized (4:1) to tapentadol ER (100 mg to 250 mg twice daily) or oxycodone CR (20 mg to 50 mg twice daily). There were no formal statistical comparisons between treatment groups. The proportions of patients who discontinued the study in the tapentadol ER and oxycodone CR groups were 54% and 65%, respectively.
• One 12-week, OL, non-inferiority phase IIIb/IV RCT (Baron 2016, N = 258) in patients with low back pain with a neuropathic component randomized (1:1) to tapentadol ER (50 mg to 250 mg twice daily) or oxycodone/naloxone PR (10 mg/5 mg to 40 mg/20 mg plus 10 mg oxycodone PR twice daily). The proportions of patients who discontinued the study in the tapentadol ER and oxycodone/naloxone PR groups were 34% and 63%, respectively. Patients in the oxycodone/naloxone PR group could switch to a separate tapentadol ER escape arm at any time, but patients in the tapentadol ER group could not switch to another group.
• One four-week, DB, non-inferiority RCT (Imanaka 2013; N = 343) in patients with cancer pain randomized (1:1) to tapentadol ER (25 mg to 250 mg twice daily) or oxycodone CR (5 mg to 40 mg twice daily). The proportions of patients who discontinued the study in the tapentadol ER and oxycodone CR groups were 33% and 29%, respectively.
• One eight-week, OL RCT (Imanaka 2014; N = 100) in patients with cancer pain whose pain was already controlled with an opioid and who were randomized (1:1) to tapentadol ER (25 mg to 250 mg twice daily) or morphine SR (10 mg to 70 mg twice daily). The proportions of patients who discontinued the study in the tapentadol ER and morphine SR groups were 44% and 42%, respectively.
• One six-week, DB RCT (Kress 2014; N = 505) in patients with cancer pain. Patients were initially randomized (2:1) to tapentadol ER (100 mg to 250 mg twice daily) or morphine sulphate CR (40 mg to100 mg twice daily) for a two-week, parallel-group titration phase followed by a randomized withdrawal maintenance phase for patients originally randomized to tapentadol ER. Thus, comparisons of tapentadol ER with morphine sulphate CR were limited to two weeks. The proportion of patients who discontinued during the titration phase was 18% in both treatment groups.

In the five chronic non-cancer pain trials, randomization was preceded by washout of prior analgesic medication. Informative direct comparisons between tapentadol ER and long-acting opioids were only available for oxycodone CR and oxycodone/naloxone PR. Statistical comparisons between tapentadol ER and oxycodone CR were not controlled for multiplicity and were considered exploratory in studies PAI-3008, PAI-3009, and PAI-3011. Further, the comparison with morphine SR (Imanaka 2014) was limited by the lack of a formal statistical comparison, and the comparison with morphine CR (Kress 2014) was limited by the two-week treatment duration.

The common limitations potentially significantly impacting internal validity were: substantial and unbalanced amounts of missing data from early study discontinuations, short durations of most of the trials (with titration periods shorter than would be expected in clinical practice), lack of blinding in some trials coupled with the use of subjective outcomes, lack of control for type I error, and potential biases introduced by approaches for imputing missing data. In the non-cancer pain trials, the most common reasons for discontinuing treatment were AEs, lack of efficacy, and patient choice with withdrawal due to AEs (WDAEs) accounting for most of the imbalances between treatment groups.

It is unclear whether the patients in the non-cancer pain trials would be considered appropriate candidates for continuous, long-term opioid therapy in the current Canadian setting. Only one of these trials (Baron 2016) specified in the entry criteria that patients had to require treatment with an opioid analgesic according to the investigator. In the cancer pain trials, the intervention may not be relevant to the clinical setting as treatment durations were eight weeks or less and substantial proportions of patients received dosages of tapentadol ER that were below the minimum recommended dosage.

No trials comparing tapentadol ER with hydromorphone CR, methadone, transdermal fentanyl, transdermal or buccal film buprenorphine, tramadol ER, or codeine CR met the review criteria.

Outcomes

Outcomes were defined a priori in the CDR systematic review protocol. Of these, the committee discussed the following: pain intensity (using an 11-point numeric rating scale [NRS]), health-related QoL (variously including the 36-Item Short Form Health Survey [SF-36], EuroQol 5-Dimension 3-Level [EQ-5D-3L], and the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), AEs, gastrointestinal symptoms, and WDAEs. The primary outcome in five trials (PAI-3008, PAI-3009, PAI-3011, Baron 2016, and Imanaka 2013) was change in pain intensity on an 11-point NRS. In Baron 2016, change in Patient Assessment of Constipation Symptoms (PAC-SYM) total score was a co-primary outcome. The primary outcome in Imanaka 2014 was the proportion of patients who maintained pain control (based on an 11-point NRS pain intensity score and rescue medication use) and the primary outcome in Kress 2014 was pain control during the randomized withdrawal phase. Study PAI-3007 measured change in 11-point NRS pain intensity, but was primarily a safety study.

• The 11-point NRS for pain intensity is an ordinal scale from 0 to 10 with 0 corresponding to “no pain” and 10 corresponding to “pain as bad as you can imagine.” Estimated minimal clinically important differences (MCIDs) range from 1.1 to 2.2 points in patients with various types of chronic pain.
• The EQ-5D-3L is a generic health-related QoL measure, which includes an index score, on which scores less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1.00 are assigned to the health states “dead” and “perfect health,” respectively. Estimates of MCID for the EQ-5D-3L index score in general have ranged from 0.033 to 0.074 and MCIDs specific to patients with chronic pain were not found. The EQ-VAS is a 20 cm visual analogue scale (VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” An MCID for the EQ-VAS in patients with chronic pain was not found by CDR.
• The SF-36 is a 36-item, general health status instrument that can provide two component summaries, the physical component summary (PCS) and the mental component summary (MCS). The PCS and MCS scores range from 0 to 100 with higher scores indicating better health status. The MCID for the SF-36 MCS and PCS is typically between 2.5 and 5 points. MCIDs in patients with chronic pain were not found for the SF-36 MCS and PCS.
• The WOMAC consists of 24 self-administered items rated on an ordinal scale of 0 to 4, with 0 corresponding to the lowest level of symptoms of physical disability. The subscales assess pain, physical function, and joint stiffness due to knee and hip osteoarthritis. The global score ranges from 0 to 96, with higher scores indicating greater levels of symptoms or physical disability and MCIDs of 0.51 to 1.33 for worsening and 0.67 to 0.75 for improvement.
• The PAC-SYM is a self-administered instrument containing 12 items with a recall period of two weeks. Each item asks about the severity of a symptom and is rated on a 5-point categorical scale ranging from “absent” (0) to “very severe” (4). The overall and subscale scores are calculated as the mean score of the individual items, yielding a possible range of 0 to 4 for each score. Estimates of the MCID for the PAC-SYM overall score range from −0.52 to −0.63.

Efficacy

Harms (Safety)

Indirect Treatment Comparisons

Due to the lack of sufficient head-to-head trials of tapentadol versus opioids other than oxycodone CR, oxycodone/naloxone PR, morphine SR, and morphine sulphate CR for chronic pain management, a search for ITCs was conducted to provide indirect evidence on the efficacy and safety of the available opioids in the study population. Two network meta-analyses (NMAs) were identified for this review. Different approaches and statistical models were adopted in the two NMAs; however, a major limitation of both NMAs was the decision to combine all doses and formulations of each drug and treat them as a single intervention in the analysis. The combination of immediate and ER formulations in the NMAs provides no evidence specific to tapentadol ER, the study drug under review; thus, the usefulness of the results of these analyses is compromised.

Cost and Cost-Effectiveness

Tapentadol ER tablets are available in 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg strengths. The submitted price of tapentadol ER is based on dose: 50 mg ($1.04), 100 mg ($1.56), 150 mg ($2.09), 200 mg ($2.71), and 250 mg ($3.75). At the recommended dose range of 100 mg to 250 mg twice daily, the cost of tapentadol ER is $3.12 to $7.50 per day, or $1,140 to $2,738 per year.

The manufacturer submitted a probabilistic Markov state-transition cost-utility analysis comparing tapentadol ER with long-acting oral preparations of oxycodone, hydromorphone, and morphine in adult patients with pain severe enough to require daily, continuous, long-term opioid use that is opioid responsive and for which alternative treatment options are inadequate. The model consisted of five health states: treatment with no AEs, treatment with tolerant AEs, lack of efficacy discontinuation, AE discontinuation, and treatment switch. Transitions between health states were derived from a head-to-head RCT (PAI-3011) for tapentadol ER and oxycodone, and a published NMA for hydromorphone and morphine. The perspective was that of a Canadian health care payer, with weekly cycles over a one-year time horizon. Due to the short time horizon, no discounting was applied to costs or clinical outcomes. In their probabilistic base case, the manufacturer estimated that tapentadol ER was associated with more quality-adjusted life-years (QALYs) and lower costs than oxycodone, and was thus dominant over oxycodone. When compared with hydromorphone and morphine, tapentadol ER was associated with an incremental cost-utility ratio of $1,721 per QALY and $15,833 per QALY, respectively.

CADTH identified a number of limitations with the model submitted by the manufacturer:

• The relative treatment effects between tapentadol ER, hydromorphone, and morphine were derived by using odds ratios from an NMA. The NMA combined all doses and formulations of each drug as a single intervention and did not provide comparative clinical evidence specific to long-acting opioid formulations.
• The drug costs provided were inconsistent with the doses used to determine efficacy in the model, biasing costs in favour of tapentadol ER.
• The utility value assigned to the treatment switch health state was set to baseline utility values reported in the trials, in effect, assuming patients would gain no clinical benefit from switching to a new opioid despite incurring the costs of the new treatment for the remaining duration of the model.
• Assumptions pertaining to opioid switching in patients who discontinue therapy due to lack of efficacy or AEs do not align with clinical practice, including: instantaneous switching, averaging the costs of all comparators to determine drug costs within the switch state, and patients continuing on the same morphine equivalent dose after switching.
• Transition probabilities and event rates were assumed linear despite clinical data suggesting otherwise. Event rates observed in the 15-week trial were extrapolated to one year, thereby overestimating discontinuation in the later cycles of the model, which may bias against the comparators.
• Some long-acting opioid comparators that may be of interest were absent.

Given the uncertainty associated with the available clinical data for tapentadol ER compared with long-acting formulations of morphine and hydromorphone, the CADTH base-case reanalysis focused on the pairwise comparison between oxycodone CR and tapentadol ER for which direct clinical evidence was available. CADTH reanalysis further revised drug dosages to be consistent with the trial, assumed a higher utility value for patients who switch opioids, adjusted post-switching treatment costs, and revised rates of discontinuation beyond week 15 to reflect the available clinical trial data.

Based on CADTH reanalysis, the incremental cost-utility ratio for tapentadol ER was $45,847 per QALY gained when compared with oxycodone CR, over a one-year time horizon. At a willingness-to-pay threshold of $50,000 per QALY, the probability of tapentadol ER being cost-effective was 52%. The long-term cost-effectiveness of tapentadol ER remains unknown. The economic analysis could only consider the cost-effectiveness of tapentadol ER with long-acting formulations of morphine and hydromorphone in an exploratory analysis, and was unable to address its cost-effectiveness compared with long-acting oral formulations of tramadol or codeine.