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Tapentadol for severe acute pain

Source agency:

NHSC

Date of Submission:

15/12/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Tapentadol (Palexia)

Technology - description:

Tapentadol (Palexia) is an oral centrally acting analgesic with a dual mechanism of action as a µ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). MOR agonists act at various levels in the pain pathway by inhibiting the transmission of the pain signal, the emotional aspect of pain and pain realisation. Noradrenaline reuptake inhibitors are sometimes used in pain management to potentiate the effect of opioids such as morphine. The inhibition of noradrenaline reuptake facilitates monoaminergic transmission in descending pain inhibitory pathways in the spinal cord. Tapentadol may have a lower potential for drug-drug interactions since its activity does not involve an active metabolite with analgesic activity.

Tapentadol will be a controlled drug* and is intended to substitute currently available strong centrally acting analgesics. It may also replace or be used in combination with non-opioid analgesics. The company state that it is difficult to define the anticipated average daily dosing of tapentadol, but it is likely to be 50-100mg every 4-6 hours with a maximum dose of 600mg as used in a phase II trial(1).

*Use is regulated by the Misuse of Drugs Act (Home Office legislation).

Company or developer:

Grunenthal.

Reason for database entry:

Tapentadol is an analgesic drug that may have comparable analgesic efficacy and tolerability to other opioids. It may demonstrate a lower incidence of opioid receptor related side effects such as nausea, vomiting, constipation, and respiratory depression. This is thought to be due to its low affinity to the MOR. Tapentadol may therefore offer a new option for patients with acute pain.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Nearly established

Licensing, reimbursement and other approval:

Phase III clinical trials completed.

Technology - type(s):

Drug

Technology - use(s):

Combination, Therapeutic

Patient Indication & Setting

Patient indications:

Adults with severe acute pain requiring centrally acting analgesics.

Disease description and associated mortality and morbidity:

Pain is a major symptom of many medical conditions and is a multi-dimensional subjective experience(2) . Acute pain can be defined as pain of sudden onset that is often severe (3) . A wide variety of situations may produce acute pain, including major or minor trauma (e.g. severe crush injuries, amputation, fractures or sprains), surgery, acute medical conditions (e.g. myocardial infarction or acute pancreatitis), physiological processes (e.g. labour) and also pathological events in patients with chronic pain. Acute pain is of limited duration and usually ceases when the wound heals or the medical condition improves (3). The severity of pain can be assessed by visual analogue scales, verbal pain scales, and psychosocial assessment.

Number of Patients:

It is difficult to estimate the potential number of patients who may be eligible for tapentadol in England and Wales. Taking the pain models used in the tapentadol clinical trial programme as examples of patients who may be eligible, the numbers of finished consultant episodes for orthopaedic operations (OPCS W01-W99, O06-O10), hysterectomies (OPCS Q07, Q08) and dental operations (OPCS F08-F17, F63) in 2008/09 were 794,984, 38,159 and 203,770 respectively giving a total of 1,036,913 operations which may have required the use of opioids. This figure is likely to be an underestimate of potentially eligible patients since the total number of procedures in the same year was 9,274,423 and the incidence of severe acute postoperative pain has been estimated at 11% of all patients in the first 24 hours after major surgery (4).

Within primary care, approximately £229 million was spent in 2008 on opioid analgesics (almost £465 million on all analgesics), with almost 16 million prescriptions dispensed in England and Wales(5)(6). However an unknown proportion of these will be for chronic rather than acute pain conditions.

Technology - specialities(s):

Anaesthetics, pain relief, ITU

Technology - setting(s):

General hospital and ambulatory care

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Additive and substitution

Current Technology:

There is evidence that patients benefit from the use of multimodal analgesia after surgery.
Opioids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol), local anaesthetics, and other non-opioid analgesics, are used either singly or in combination depending on local policies, clinician experience, patient comorbidities and response.

Health Impact:

Reduction in associated morbidity: may be lower incidence of opioid associated AEs (speculative).

Diffusion:

 

Cost, infrastructure and economic consequences:

The cost of tapentadol is not yet known. The cost of oral morphine doses of 10mg and 100mg is between £0.07 and £0.65 (7).

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Trial: NCT00364247; post bunionectomy pain; tapentadol IR (immediate release) vs oxycodone or placebo; phase III.
Sponsor: Johnson and Johnson, Grunenthal.
Status: Published.
Source of information: Publication(8).
Location: USA.
Design: Randomised, controlled.
Participants and schedule: n=603; adults; postoperative pain following first metatarsal bunionectomy with osteotomy; moderate to severe;
≥4-point intensity on 11-point numerical rating scale (NRS).
Randomised to tapentadol IR 50mg, 75mg or 100mg, oxycodone IR 15mg, or placebo every 4-6 hrs for 72 hrs.
Follow-up : 72 hrs active treatment period, 9 days follow up.
Primary outcome: Sum of pain intensity difference over 48 hrs (SPID48).
Secondary outcomes: SPID over 12, 24 and 72 hrs; sum of total pain relief and sum of pain intensity difference (SPRID) over 12, 24, and 72 hrs; total pain relief (TOTPAR) over 12, 24, 48, and 72 hrs; time to perceptible, meaningful and confirmed perceptible pain relief; time to first rescue medication use.
Key results: For tapentadol 50mg, 75mg, 100mg, and oxycodone respectively vs placebo:
mean (SD) SPID48 values: 119.1 (125.86), 139.1 (118.93), 167.2 (98.99), 172.3 (110.86) vs 24.5 (120.93), all p<0.001; ≥30% reduction in pain intensity at 48 hrs: 65%, 68%, 79% and 78% vs 40% (p<0.001).
Adverse effects (AEs): Overall incidence of nausea, vomiting and constipation for tapentadol 50mg, 75mg, 100mg and oxycodone 15mg respectively: 46% 46%, 59% and 73%.

Trial: NCT00613938; post bunionectomy pain; tapentadol IR vs oxycodone or placebo; phase III.
Sponsor: Johnson and Johnson, Grunenthal.
Status:Published.
Source of information Publication(9).
Location: USA.
Design: Randomised, controlled.
Participants and schedule: n=901; adults; postoperative pain following first metatarsal bunionectomy with osteotomy; moderate to severe;
≥4-point intensity on 11-point NRS.
Randomised to tapentadol IR 50mg or 75mg, oxycodone IR 10mg, or placebo every 4-6 hrs for up to 72 hrs.
Follow-up: 72 hrs active treatment period, 30 days safety follow up.
Primary outcome: SPID48.
Secondary outcomes: SPID72; SPRID72.
Key results: For tapentadol 50mg, 75mg, and oxycodone respectively:
least squares mean difference (LSMD) in SPID48 from placebo (95% CI): 62.4 (39.01-85.73), 84.6 (61.29-107.96), and 81.5 (58.13-104.79), all p<0.001.
Adverse effects (AEs): Nausea and/or vomiting for tapentadol 50mg, 75mg vs oxycodone: 35% (p<0.001), 51% (p=0.057) and 59%.

Trial: NCT00361582; end-stage joint disease, tapentadol IR vs oxycodone or placebo; phase III.
Sponsor: Grunenthal.
Status : Published.
Source of information: Publication(10).
Location: USA.
Design: Randomised, controlled.
Participants and schedule: n=666; adults; osteoarthritis; end-stage degenerative joint disease; candidate for primary joint replacement surgery (hip or knee).
Randomised to tapentadol 50mg or 75mg, oxycodone 10mg, or placebo every 4-6 hrs for 10 days.
Follow-up: 10 days active treatment period, 5 days follow up.
Primary outcome: Sum of pain intensity difference over 5 days (SPID5).
Secondary outcomes: 2 and 10-day SPID; 2, 5, and 10-day TOTPAR; tolerability.
Key results: Tapentadol 50mg, 75mg, and oxycodone respectively, LSMD from placebo:
SPID5 (95% CI): 101.2 (54.58-147.89), 97.5 (51.81-143.26), 111.9 (66.49-157.38), all p<0.001.
2 and 10-day SPID and 2, 5, and 10-day TOTPAR: statistically significant for both tapentadol groups and oxycodone (all comparisons p<0.001).
Tapentadol 50mg and 75mg respectively vs oxycodone: nausea and/or vomiting odds ratios (OR) (95% CI): 0.21 (0.128-0.339) and 0.32 (0.204-0.501); constipation: 0.13 (0.057-0.302) and 0.20 (0.098–0.398).
Treatment discontinuation for tapentadol 50mg, 75mg, oxycodone 10mg and placebo respectively: 18%, 26%, 35%, and 10%.
Adverse effects (AEs): Most frequently reported AEs: dizziness, nausea, vomiting, somnolence, constipation, fatigue, pruritis (for tapentadol 50mg, 75mg, oxycodone 10mg and placebo respectively: 52%, 71%, 84%, and 32%).

Trial: NCT00364546; low back pain or osteoarthritis (OA); tapentadol IR vs oxycodone or placebo; phase III.
Sponsor: Grunenthal.
Status: Published.
Source of information: Publication(1).
Location : USA, Canada.
Design: Randomised, controlled.
Participants and schedule: n=878; adults; lower back pain or OA pain of knee or hip; non-malignant; 3-month history; pain intensity (PI) score of 4 on NRS.
Randomised to tapentadol IR 50mg or 100mg (maximum dose 600mg per day), oxycodone IR 10mg or 15mg (max dose 90mg per day), or placebo every 4-6 hrs for 90 days.
Follow-up : 90 days active treatment period, 3 days follow up.
Primary outcome: AEs; clinical opioid withdrawal scale (COWS), subjective opioid withdrawal scale (SOWS) assessments, 12-lead ECG.
Secondary outcomes: Principal Investigator assessments and patient global impression of change (PGIC).
Key results: Incidence of nausea, vomiting, and constipation significantly lower (p<0.001) in tapentadol (18%, 17%, and 13%, respectively) vs oxycodone IR (29%, 30%, and 27%, respectively).
COWS or SOWS for tapentadol IR vs oxycodone respectively: 17% vs 29%. Mean total SOWS score: 6.9 vs 8.7 (no significant difference).
For tapentadol and oxycodone: mean baseline PI scores: 7.0 and 7.2; mean PI scores at end of study 4.9 and 5.2; PGIC as ‘improved’: 66% vs 62% (no significant difference).
Adverse effects (AEs): As above.

Trial: Post dental surgery pain; tapentadol IR vs morphine or placebo; phase II.
Sponsor: Grunenthal.
Status: Published.
Source of information: Publication(11).
Location: USA.
Design: Randomised, controlled.
Participants and schedule: n=400; adults; postsurgical dental pain; moderate to severe on visual analogue scale (VAS).
Randomised to single dose tapentadol 25mg, 50mg, 75mg, 100mg or 200mg, morphine 60mg, ibuprofen 400mg, or placebo.
Follow-up: 24 hrs after surgery.
Primary outcome: TOTPAR-8.
Secondary outcomes: TOTPAR-4 and onset of analgesia.
Key results: For tapentadol 25mg, 50mg, 75mg, 100mg, 200mg, morphine, ibuprofen respectively:
Mean TOTPAR-8 score (SD) vs placebo (4.7 (7.3)): 6.3 (8.4), 7.9 (8.1), 9.7 (8.5), 11.6 (8.2), 15.3 (7.5), 13.8 (10.3), 17.9 (9.9).
Mean TOTPAR-4 score (SD) vs placebo (2.0 (2.9): 2.6 (3.5), 3.7 (3.6), 4.3 (3.7), 5.2 (3.7), 7.1 (3.5), 5.8 (4.6), 8.2 (4.6).
Proportion experiencing 50% pain relief for tapentadol 25mg, 50mg, 75mg, 100mg, 200mg, morphine, ibuprofen and placebo: 32%, 46%, 46%, 65%, 88%, 65%, 77% and 26%.
Adverse effects (AEs): Incidence of AEs lower with all doses of tapentadol IR vs morphine 60mg (but not statistically significant).


Trial: NCT00806247; post bunionectomy pain; tapentadol IR vs oxycodone or placebo; phase II.
Sponsor: Grunenthal.
Status: Published.
Source of information: Publication(12).
Location: USA.
Design: Randomised, controlled.
Participants and schedule: n=269; adults; postoperative pain following first metatarsal bunionectomy with osteotomy; moderate to severe; ≥4-point intensity on 11-point NRS.
Randomised to tapentadol IR 50mg, 75mg or 100mg, oxycodone IR 15mg, or placebo every 4-6 hrs for 72 hrs.
Follow-up: 72 hrs active treatment period.
Primary outcome: Sum of pain intensity (SPI) over 24 hrs on day 3.
Secondary outcomes: Safety.
Key results: For tapentadol 50mg, 100mg, and oxycodone 10mg vs placebo respectively: mean SPI-24 (SD): 33.6 (19.7, p=0.0133), 29.2 (15.2, p=0.0001), 35.7 (17.2, p=0.0365) vs 41.9 (17.7).
Adverse effects (AEs): AEs for tapentadol vs oxycodone: nausea 46.3% vs 71.6%; dizziness 32.8% vs 17.9%; vomiting 16.4% vs 38.8%; constipation 6.0% vs 17.9%; and somnolence 28.4% vs 26.9%.

Trial: NCT00364533; post hip replacement pain, tapentadol IR vs oxycodone or placebo; phase III.
Sponsor: Grunenthal.
Status: Trial terminated.
Source of information: Trial registry(13).
Location: USA, EU (inc. UK).
Design: Randomised, controlled.
Participants and schedule: n=365; adults; postsurgical pain following hip replacement; moderate to severe; ≥4-point intensity on 11-point NRS.
Randomised to tapentadol IR 50mg, 75mg or 100mg, oxycodone IR 10mg, or placebo every 4-6 hrs for 72 hrs.
Follow-up : 72 hrs active treatment period.
Primary outcome: SPID48.
Secondary outcomes: Time to first rescue medication, SPID12, SPID24 and SPID72.
Key results: Terminated due to small numbers of participants analysed. Discontinuation rate for tapentadol 50mg, 75mg, 100mg, oxycodone and placebo respectively: 55%, 56%, 60%, 46% and 68%.
Expected reporting date -


Trial: NCT00478023; postoperative hysterectomy pain; tapentadol IR vs morphine or placebo; phase III.
Sponsor: Grunenthal.
Status: Trial complete but unpublished.
Source of information: Trial registry(14).
Location: EU, Russian Federation, Serbia and Montenegro, and Ukraine.
Design: Randomised, controlled.
Participants and schedule: n=854; pain following hysterectomy; moderate to severe; ≥4-point intensity on 11-point NRS.
Randomised to tapentadol IR 50mg, 75mg or 100mg, morphine 20mg, or placebo every 4-6 hrs for 72 hrs.
Follow-up: 72 hrs active treatment period.
Primary outcome SPID24.
Secondary outcomes: SPID48.
Key results -
Expected reporting date: Not known.

Trial: NCT00609466; postoperative bunionectomy pain; tapentadol IR vs morphine or placebo; phase III.
Sponsor : Grunenthal.
Status : Trial complete but unpublished.
Source of information: Trial registry (15).
Location: USA
Design: Randomised, controlled.
Participants and schedule: n=279; adults; postoperative pain following first metatarsal bunionectomy with osteotomy; moderate to severe; ≥4-point intensity on 11-point NRS.
Randomised to tapentadol IR 75mg or morphine 20mg, or placebo every 4-6 hrs for 72 hrs.
Follow-up: 72 hrs active treatment period.
Primary outcome: SPID48.
Secondary outcomes: Time to first rescue medication, SPID6, SPID12, SPID24 and SPID72.
Key results: -
Expected reporting date: Not known.

Economic evaluation:

 

Ongoing research:

 

Ongoing or planned HTA:

 

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

(1)Hale M, Upmalis D, Okamoto A et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: A randomized, double-blind study. Current Medical Research and Opinion 2009;25(5):1095-104.
(2)Melzack R and Wall P. Handbook of pain management. A clinical companion to Wall and Melzack’s textbook of pain. Edinburgh: Churchill Livingstone; 2003.
(3)The Royal College of Anaesthetists. Guidance on the provision of anaesthetic services for acute pain management in: Guidelines for the provision of anaesthetic services. Chapter 6 acute pain services. 2009.
(4)Dolin SJ, Cashman JN and Bland JM. Effectiveness of acute postoperative pain management: I. Evidence from published data. British Journal of Anaesthesia 2002; 89(3):409–23.
(5)The NHS Information Centre. Prescription cost analysis. England; 2008: http://www.ic.nhs.uk/statistics-and-data-collections/primary-care/prescriptions Accessed 9 November 2009.
(6)Prescribing Services. Prescription cost analysis. Wales; 2008: http://www.wales.nhs.uk/sites3/page.cfm?orgid=428&pid=13533 Accessed 9 November 2009.
(7)British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2009.
(8)Daniels SE, Upmalis D, Okamoto A et al. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy)pain. Current Medical Research and Opinion 25(3) 2009;(3):765-76.
(9)Daniels S, Casson E, Stegmann J-U, Oh C et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Current Medical Research and Opinion 2009;25(6):1551-61.
(10)Hartrick C, Van H, I, Stegmann JU et al. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clinical Therapeutics 2009; 31(2):260-71.
(11) Kleinert R, Lange C, Steup A et al. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesthesia & Analgesia 2008;107(6):2048-55.
(12) Stegmann J-U, Weber H, Steup A et al. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopaedic (bunionectomy) surgery. Current Medical Research and Opinion 2008;24(11):3185-96.
(13) ClinicalTrials.gov. A study to evaluate the effectiveness and safety of tapentadol in the treatment of acute pain after hip replacement surgery compared with oxycodone and placebo followed by a voluntary open-label extension for safety. http://www.clinicaltrials.gov/ct2/results?term=NCT00364533 Accessed 26 October 2009.
(14) ClinicalTrials.gov. A study to evaluate the efficacy and safety of CG5503 in the treatment of acute pain after abdominal hysterectomy compared with morphine and placebo. http://www.clinicaltrials.gov/ct2/results?term=NCT00478023 Accessed 26 October 2009.
(15) ClinicalTrials.gov. A trial to evaluate the efficacy and safety of CG5503 in the treatment of acute pain after bunionectomy compared with morphine and placebo. http://www.clinicaltrials.gov/ct2/results?term=NCT00609466 Accessed 26 October 2009.

Notes: