Suffolk Drug & Therapeutics Group · 2016-01-13 · buprenorphine (Transtec patches, sublingual tablets) [8] Place in therapy Tapentadol IR has been trialled in post bunionectomy,

Review prepared by Katie Smith, East Anglia Medicines Information Service for NHS Suffolk May be freely copied by NHS agencies Not to be used for promotional purposes

Suffolk PCT Drug & Therapeutics Committee New Medicine Report

This drug has been reviewed because it is a product that may be prescribed in primary care.

Medicine Tapentadol

Trade names – Palexia / Palexia SR Manufacturer - Gruenenthal

Document status Reviewed at September 2011 Suffolk D&TC meeting

Date of last revision 26 September 2011

Traffic light decision March 2011: Blue – GP prescribed September 2011:- Blue – Primary Care

Prescribers rating March 2011: 5 - Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. September 2011:- Possibly helpful- The product has minimal additional value, and should not change prescribing habits except in rare circumstances

QIPP rating May 2011: Double red

Mechanism of action Dual mode analgesic that inhibits norepinephrine reuptake and has mu opioid receptor agonism. [1-7]

Medicine class BNF 4.7 – opioid analgesic, and a controlled drug [8]

Indication Immediate release (IR) 50mg & 75mg tablets - relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. [1-2] Sustained release (SR) 50mg, 100mg, 150mg, 200mg, 250mg tablets - management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. [3-7]

Dosage IR oral tablets: 50 mg, 75 mg [1-2] The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient. Patients should start treatment with single doses of 50 mg tapentadol as film-coated tablet administered every 4 to 6 hours. Higher starting doses may be necessary depending on the pain intensity and the patient's previous history of analgesic requirements. On the first day of dosing, an additional dose may be taken as soon as one hour after the initial dose, if pain control is not achieved. The dose should then be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician. Daily doses greater than 700 mg tapentadol on the first day of treatment and maintenance daily doses greater than 600 mg tapentadol have not been studied and are therefore not recommended. As soon as stable dosing regimen is achieved and longer treatment is anticipated, the possibility of switching the patient to therapy with the prolonged-release tablets (Palexia SR) should be considered. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. The tablets should be taken with sufficient liquid and with or without food. SR oral tablets: 50mg, 100mg, 150mg, 200mg, 250mg [3-7] - The dosing regimen


should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient. Tapentadol SR should be taken twice daily, approximately every 12 hours. Patients should start treatment with single doses of 50 mg tapentadol as prolonged-release tablet administered twice daily. When switching from opioids to tapentadol SR and choosing the initial dose, the nature of the previous medicinal product, administration and the mean daily dose should be taken into account. This may require higher initial doses of tapentadol SR for patients currently taking opioids compared to those not having taken opioids before initiating therapy with tapentadol SR. After initiation of therapy the dose should be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician. Experience from clinical trials has shown that a titration regimen in increments of 50 mg tapentadol as prolonged-release tablet twice daily every 3 days was appropriate to achieve adequate pain control in most of the patients. Total daily doses of tapentadol SR greater than 500 mg tapentadol have not yet been studied and are therefore not recommended. The tablets have to be taken whole, not divided or chewed. They should also be taken with sufficient liquid and with or without food. Patients with mild or moderate renal impairment and mild hepatic impairment do not require a dosage adjustment. [1-7] Tapentadol should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at the lowest available dose strength, i.e. IR 50 mg tapentadol as film-coated tablet, and not be administered more frequently than once every 8 hours or SR 50 mg tapentadol as film-coated tablet, and not be administered more frequently than once every 24 hours. At initiation of therapy a daily dose greater than IR 150 mg tapentadol or SR 50 mg tapentadol as film-coated tablet is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval. [1-7] Tapentadol has not been studied in controlled efficacy trials in patients with severe renal or hepatic impairment, therefore the use in this population is not recommended. [1-7] Care should be taken when selecting an initial dose in elderly patients as they are more likely to have decreased renal and hepatic function. [1-7] There is very limited data on use of tapentadol in pregnant women. Tapentadol should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. [1-7] Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Due to the mu-opioid receptor agonist activity of tapentadol, neonates whose mothers have been taking tapentadol should be monitored for respiratory depression. [1-7] There is no information on excretion of tapentadol in to breast milk. Therefore, tapentadol should not be used during breast-feeding. [1-7] The safety and effectiveness of tapentadol in pediatric patients less than 18 years of age has not been established therefore tapentadol is not recommended in this population. [1-7]

Treatment alternatives Morphine, oxycodone, hydromorphone, fentanyl patches, methadone,


buprenorphine (Transtec patches, sublingual tablets) [8]

Place in therapy Tapentadol IR has been trialled in post bunionectomy, hysterectomy and dental surgery patients with acute pain and therefore may be an option in secondary care. The IR preparation has also been studied in patients with knee osteoarthritis (OA) and low back pain. [9-14] Tapentadol SR has been trialled in patients with chronic pain due to knee OA and low back pain. [15-18] Pain relief after surgery should be adjusted for each patient and each situation. Multimodal regimens, using several classes of analgesic, and ideally more than one route, are now generally favoured. Pre-operative evaluation of the patient, and frequent assessment of pain intensity after surgery (both to allow appropriate analgesia, and to detect possible complications) are fundamental. Patients undergoing minor surgery can be adequately managed with oral analgesics, such as paracetamol, NSAIDs, tramadol, and oxycodone. Opioid analgesics, in particular morphine, are the mainstay of treatment for moderate to severe postoperative pain. Opioid dose should be individually titrated. [19] The Clinical Knowledge Summary on osteoarthritis states that regular dosing with paracetamol and topical nonsteroidal anti-inflammatory drugs (NSAIDs) to substitute or supplement paracetamol should be used initially. If paracetamol and/or topical NSAIDs are ineffective consider standard oral NSAIDs or coxibs. If an opioid is needed codeine should be tried first, alone or together with paracetamol. Obtain specialist advice before prescribing stronger opioids such as fentanyl or buprenorphine patches, or morphine. [20] The Clinical Knowledge Summary on low back pain states that for first-line analgesia offer paracetamol. If paracetamol is insufficient, offer a standard nonsteroidal anti-inflammatory drug (NSAID), or a coxib. For additional analgesia, consider the following options: paracetamol combined with an NSAID/coxib or adding a weak opioid such as codeine, dihydrocodeine, or tramadol. For chronic pain not responding to first-line analgesics and additional analgesics consider offering a trial of a tricyclic antidepressant such as amitriptyline, nortriptyline, or imipramine. A strong opioid is rarely necessary. If a strong opioid (such as standard-release morphine) is to be used prescribe it for a short period, and step down to a weak opioid when appropriate. [21] Approximately 20% of patients taking opioids discontinue therapy due to adverse effects. [22] Use of tapentadol may be considered if patients can not tolerate currently used strong opioids. Tapentadol SR is accepted for restricted use within NHS Scotland for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. The SMC restriction is to use patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. [23]

Future alternatives None known

Evidence for use Details of the published and unpublished clinical trials for the IR and SR formulations are in appendices 1 and 2 respectively. Tapentadol IR and SR has been compared with oxycodone in most published studies, [9-12, 14, 15-18] one study used morphine and ibuprofen as the comparators. [13] The studies show that tapentadol IR and SR both have comparable analgesic efficacy and tolerability to oxycodone. Tapentadol demonstrates a lower incidence of opioid receptor related side effects such as constipation, nausea and vomiting.


Three phase III studies with identical methodology comparing the efficacy and tolerability of tapentadol SR (100-250mg BD) with oxycodone SR (20-50mg BD) for 12 weeks [15-17] are included in a pooled analysis. [ 24] Two of the trials are in patients with osteoarthritis of the knee [15, 16] and 1 study is in patients with low back pain. [17] One of the studies in knee osteoarthritis has not been published but some details and data are available via the ClinicalTrials.gov website. [16] The analysis concludes that tapentadol SR 100-250mg twice daily has similar efficacy (non-inferior) and a superior gastrointestinal tolerability profile with oxycodone SR 20-50mg twice daily. Secondary endpoints for improvement in health status (SF36 and EQ-5D) were statistically significantly better for tapentadol (p ≤ 0.048) compared to oxycodone. This may be a reflection of the poorer tolerability of oxycodone and the higher rate of treatment discontinuations. [24] There is one published open label phase 3 trial that has assessed safety and tolerability of tapentadol in patients with chronic pain due to knee or hip osteoarthritis or low back pain for up to 1 year. [18] The median duration of treatment with tapentadol was 268 days vs. 59 with oxycodone. Tapentadol also demonstrated better GI tolerability. Compared to tapentadol, the incidence of GI adverse effects leading to discontinuation was ~2.5 times greater with oxycodone and the incidence of constipation leading to discontinuation was ~4.5 times greater with oxycodone.

NNT Not calculated

Contraindications / cautions [from refs 1-7]

Patients with hypersensitivity to tapentadol or to any of the excipients. Situations where active substances with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia. Any patient who has or is suspected of having paralytic ileus. Patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances. Tapentadol has a potential for abuse and addiction. This should be considered when prescribing or dispensing Palexia in situations where there is concern about an increased risk of misuse, abuse, addiction, or diversion. At high doses or in mu-opioid receptor agonist sensitive patients, tapentadol may produce dose-related respiratory depression. Therefore, tapentadol should be administered with caution to patients with impaired respiratory functions. Tapentadol should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. Tapentadol should be used with caution in patients with head injury and brain tumours. Tapentadol has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical trials. However, like other analgesics with mu-opioid agonist activity tapentadol should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures. Active substances with mu-opioid receptor agonist activity may cause spasm of


the sphincter of Oddi. Tapentadol should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Side effects [from refs 1-7]

Tapentadol may have major influence on the ability to drive and use machines due to the fact that it may adversely affect central nervous system functions. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilisers. Patients should be cautioned as to whether driving or use of machines is permitted. The adverse drug reactions that were experienced by patients in the placebo controlled trials performed with tapentadol were predominantly of mild and moderate severity. The most common adverse events (reported by ≥ 10% in any tapentadol dose group) were: nausea, dizziness, headache, constipation, vomiting and somnolence. The SPCs list a number of other common, uncommon and rare adverse effects. The most common reasons for discontinuation due to adverse events in 9 phase 2/3 studies (reported by ≥ 1% in any tapentadol dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for tapentadol- and placebo-treated patients, respectively. [25] 76% of tapentadol-treated patients from the nine studies experienced adverse events. [25] Clinical trials performed with tapentadol with patient exposure up to 90 days have shown little evidence of withdrawal symptoms upon abrupt discontinuations and these were generally classified as mild, when they occurred. Nevertheless, physicians should be vigilant for symptoms of withdrawal and treat patients accordingly should they occur. The risk of suicidal ideation and suicides committed is known to be higher in patients suffering from chronic pain. In addition, substances with a pronounced influence on the monoaminergic system have been associated with an increased risk of suicidality in patients suffering from depression, especially at the beginning of treatment. For tapentadol data from clinical trials and post-marketing reports do not provide evidence for an increased risk.

Drug Interactions [from refs 1-7]

Tapentadol may have a lower potential for drug-drug interactions since its activity does not involve an active metabolite with analgesic activity. [1-7, 26] Only about 15% of a tapentadol dose is metabolised by the cytochrome P450 system (CYP2C9, CYP2C19, CYP2D6). [1-7] Treatment with tapentadol should be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis. Medicinal products like benzodiazepines, barbiturates and opioids (analgesics, antitussives or substitution treatments) may enhance the risk of respiratory depression if taken in combination with tapentadol. CNS depressants (e.g. opioids, benzodiazepines, antipsychotics, H1-antihistamines, alcohol) can enhance the sedative effect of tapentadol and impair vigilance. Therefore, when a combined therapy of tapentadol with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered. In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products such as selective serotonin re-uptake inhibitors


(SSRIs). There is no clinical data on the concomitant use of tapentadol with mixed mu-opioid agonist/antagonists (pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine). As with pure mu-opioid agonists, the analgesic effect provided by the mu-opioid component of tapentadol may be theoretically reduced in such circumstances. Therefore, care should be taken when combining tapentadol with these medicinal products. The major elimination pathway for tapentadol is conjugation with glucuronic acid mediated via uridine diphosphate transferase (UGT) mainly UGT1A6, UGT1A9 and UGT2B7 isoforms. Thus, concomitant administration with strong inhibitors of these isoenzymes may lead to increased systemic exposure of tapentadol. Interaction studies with active substances that potentially could affect the glucuronidation (paracetamol, acetylsalicylic acid, naproxen and probenecid) did not result in any clinically relevant effect on the serum concentrations of tapentadol. Interaction studies with substances that can affect absorption of tapentadol (omeprazole and metoclopramide) did not result in any clinically relevant effect on the serum concentrations of tapentadol. For patients on tapentadol treatment, caution should be exercised if concomitant drug administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John's Wort (hypericum perforatum)) starts or stops, since this may lead to decreased efficacy or risk for adverse effects, respectively.

Cost within PbR tariff? In tariff

Cost [from MIMS Sept 2011]

50mg IR x 56 = £24.91, 50mg IR x 28 = £12.46, 75mg IR x 56 = £37.37, 75mg IR x 28 = £18.68

50mg SR x 56 = £24.91, 50mg SR x 28 = £12.46 100mg SR x 56 = £49.82 150mg SR x 56 = £74.73 200mg SR x 56 = £99.64 250mg SR x 56 = £124.55

Comparative costs of other medicines [from MIMS Sept 2011]

Drug Dose Cost

Morphine IR Dose adjusted according to response

56 x 10mg = £5.61

Morphine SR 60 x 100mg = 39.07 (MST Continus)

Oxycodone IR Dose adjusted according to response

56 x 5mg = £11.38 56 x 10mg = £22.76 56 x 20mg = £45.51

Oxycodone SR 56 x 10mg = £24.94 56 x 20mg = £49.87 56 x 40mg = £99.77

Fentanyl patch Dose adjusted according to response

10 x 12mcg/hr to 100mcg/hr = £17.76 - £172.92

An American cost effectiveness analysis compared tapentadol IR with oxycodone IR for treatment of acute post-surgical and non-surgical pain. [27] A Markov model simulated clinical –economic outcomes for tapentadol 100mg vs. oxycodone 15mg for 3 days for acute post-surgical pain and tapentadol 50mg vs. oxycodone 10mg for 10 days for acute non-surgical pain. The model simulated changes in pain relief, occurrence of opioid related adverse effects, opioid switching, discontinuation, dose change and number of quality adjusted life days. The cost of medication was higher for tapentadol than oxycodone but there were reduced pharmacy and medical costs associated with treatment of adverse effects, opioid switching and discontinuation with tapentadol. The authors conclude that tapentadol is a cost effective alternative to doses of oxycodone that provide comparable analgesia for the treatment of acute surgical and non-surgical


pain.

Potential number of patients & usage in Suffolk PCT

Prevalence of chronic pain in the UK population is about 13% - back pain and OA pain are the most common causes. Of this population, about 12% are taking strong opioids for pain relief. [28]

Applying these figures to NHS Suffolk (population 600,000) means there are approximately 78,000 people with chronic pain, of whom about 9,360 are currently taking strong opioids.

It is difficult to estimate the potential number of patients who may be eligible for tapentadol. In 2008/2009 there were over 9,000,000 procedures in England and Wales which may have required use of opioids. The incidence of severe acute pain has been estimated at 11% of all patients in the first 24 hrs after major surgery. [26]

In primary care in 2008, approx. £229 million was spent on opioid analgesics with almost 16 million prescriptions dispensed in England and Wales. [26]

Is the drug on the WSH or IHT formularies?

WSH - tapentadol is allowed for use by the chronic pain team only, for patients with chronic, ongoing pain in whom a trial of appropriate step 3 opioids (MST) was not tolerated. IHT - No

Decisions from other bodies

Cambridgeshire JPG – double red for primary care Norfolk TAG – not assessed

Scottish Medicines Consortium – June 2011 [23] Tapentadol SR is accepted for restricted use within NHS Scotland for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. The SMC restriction is to use patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. Results of a meta-analysis of three, 12-week studies suggest that tapentadol prolonged release has improved gastrointestinal tolerability and similar efficacy compared to another long-acting opioid included as an active control. Tapentadol IR tablets are not recommended for use in NHS Scotland as a submission was not received from the manufacturer. In their submission to the SMC, the manufacturers proposed that tapentadol SR should be considered as an alternative to oxycodone MR or TD fentanyl patch in patients where morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. The evidence to support this positioning is limited. The inclusion criteria of the phase III studies required only that eligible patients were dissatisfied with their current analgesic (opioid or non-opioid) and only 34% of the meta-analysis population had received opioids within the previous 3 months. The studies also included a minority of patients with moderate pain, while the marketing authorisation for tapentadol SR stipulates use in severe pain, and there is no direct comparative data for TD fentanyl patches. Based on the more relevant subgroup analysis of patients with severe pain and prior opioid use, using the pooled data the manufacturer estimated tapentadol SR would produce a saving of £77 and quality adjusted life year (QALY) gain of 0.0045 per patient compared to oxycodone, and a saving of £201 and QALY gain of 0.00379 compared to TD fentanyl and therefore be the preferred treatment on cost-effectiveness grounds. Larger cost savings and QALY gains were estimated in the analysis using the whole pooled patient population. A key driver behind these results was the favourable AE outcomes for tapentadol SR as the relative probabilities of discontinuation associated with lack of efficacy were less favourable for tapentadol SR. Although weaknesses were identified with the health economic analysis, extensive one way sensitivity and scenario analysis demonstrated that savings and QALY gains persisted for both comparisons, therefore despite weaknesses in the clinical


evidence and other assumptions, the economic case for tapentadol SR was considered demonstrated.

Points for consideration

Tapentadol IR and SR have been compared with oxycodone in most published studies, two studies used morphine and one study used ibuprofen as the comparators.

Tapentadol IR 50-100mg has comparable analgesic efficacy and tolerability to oxycodone 10-15mg and tapentadol SR 100-250mg has comparable analgesic efficacy and tolerability to oxycodone 20-50mg. It demonstrates a lower incidence of opioid receptor related side effects such as constipation, nausea and vomiting.

Tapentadol is also being investigated for treatment of diabetic peripheral neuropathic pain and cancer pain. [26, 28, 29]

There is currently no published data on use of tapentadol in patients with cancer. One trial was terminated early and another trial is underway. NCT00505414 was terminated early, due to a recall of the morphine rescue medication and issues regarding supply of an alternative. http://www.clinicaltrials.gov/ct2/show/NCT00505414?term=NCT00505414&rank=1 NCT00472303 - A Study to Evaluate CG5503 (tapentadol ER) in the Treatment of Chronic Tumor Related Pain Compared With Placebo and Morphine is still recruting. http://www.clinicaltrials.gov/ct2/show/NCT00472303?term=NCT00472303&rank=1

The manufacturers propose that tapentadol SR should be considered as an alternative to oxycodone MR or TD fentanyl patch in patients where morphine sulphate MR has failed to provide adequate pain control or is not tolerated. The SMC considered the evidence to support this positioning as limited.

Tapentadol IR and SR have been priced so they are comparable to oxycodone IR and SR.

After a review of clinical effectiveness and health economic evidence, the SMC have accepted tapentadol SR for restricted use within NHS Scotland for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics in patients in whom morphine sulphate MR has failed to provide adequate pain control or is not tolerated. Tapentadol IR tablets are not recommended for use.

Comments sought from

Dr Mike Bailey, Ipswich hospital Dr Marcia Schofield & Dr Rajesh Munglani, West Suffolk hospital Dr Kelvin Bengston, St Elizabeth hospice Dr Jenna Kitchen, St Nicholas hospice Dr Rosemary Wade, West Suffolk Hospital Palliative Care Team

Decision review date Sept 2013

References 1. Summary of Product Characteristics. Palexia 50 mg film-coated tablets. Grunenthal Ltd. Last updated

28/03/11. http://www.medicines.org.uk/emc/medicine/24387/SPC/ 2. Summary of Product Characteristics. Palexia 75 mg film-coated tablets. Grunenthal Ltd. Last updated

28/03/11. http://www.medicines.org.uk/emc/medicine/24388/SPC/ 3. Summary of Product Characteristics. Palexia SR 50 mg prolonged-release tablets. Grunenthal Ltd. Last

updated 28/03/11. http://www.medicines.org.uk/emc/medicine/24389/SPC/ 4. Summary of Product Characteristics. Palexia SR 100 mg prolonged-release tablets. Grunenthal Ltd. Last




updated 28/03/11. http://www.medicines.org.uk/emc/medicine/24393/SPC/ 8. BNF March 2011, No. 61

http://www.clinicaltrials.gov/ct2/show/NCT00505414?term=NCT00505414&rank=1




http://www.medicines.org.uk/emc/medicine/24387/SPC/








9. Daniels S, Casson E et al. A randomised, 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 & Opinion 2009; 25 (6): 1551-61

10. Hartrick C, Van Hove I 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, randomised, double blind, active and placebo controlled study. Clinical Therapeutics 2009; 31 (2): 260-71

11. Hale M, Upmalis D et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomised, double blind study. Current Medical Research & Opinion 2009; 25 (5): 1095-1104

12. 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.

13. 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.

14. 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.

15. Afilalo M, Etropolski MS et al. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee. Clinical Drug Investigation 2010; 30 (8): 489-505

16. ClinicalTrials.gov. A Randomized Double-blind, Placebo- and Active-control, Parallel-arm, Phase III Trial With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of CG5503 Prolonged Release (PR) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee. http://clinicaltrials.gov/ct2/show/results/NCT00486811 Accessed 8 September 2011.

17. Buynak R, Shapiro DY et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010; 11(11):1787-804.

18. Wild JE, Grond S et al. Long term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Practice 2010; 10 (5): 416-27

19. Postoperative analgesia (Latest modification: 20-Aug-2010). Martindale - The Complete Drug Reference. 36

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20. Clinical Knowledge Summary – Osteoarthritis. Version 1.4, last revised in August 2008. http://www.cks.nhs.uk/osteoarthritis

21. Clinical Knowledge Summary – Low back pain without radiculopathy. Version 1.3, last revised November 2009. http://www.cks.nhs.uk/back_pain_low_without_radiculopathy

22. Candiotti KA, Gitlin MC. Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution? Current Medical Research & Opinion 2010; 26 (7): 1677-84

23. Scottish Medicines Consortium. Resubmission – tapentadol 50, 100, 150, 200 and 250mg prolonged release tablets (Palexia SR). Published 13 June 2011. http://www.scottishmedicines.org.uk/files/advice/tapentadol_Palexia_SR_RESUBMISISON_FINAL_MAY_2011_for_website.pdf

24. Lange B, Kuperwasser B et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010; 27 (6): 381-9

25. Nucynta prescribing information. Accessed on Feb 9 2011 via http://www.nucynta.com/sites/all/themes/nucynta/pdf/Nucynta-PI.pdf

26. Tapentadol (Palexia) prolonged release for severe chronic pain / Tapentadol (Palexia) for severe acute pain. National Horizon Scanning Centre, December 2009. http://www.haps.bham.ac.uk/publichealth/horizon/outputs/tech_briefings/anaesthetics.shtml

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29. Schwartz S, Etropolski M et al. Safety and efficacy of tapentadol ER in patients with painful diabetic neuropathy: results of a randomised-withdrawal, placebo controlled trial. Curr Med Res Opin 2011; 27: 151-62.

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Appendix 1 – Summary of published clinical trials with IR tapentadol

Ref No

Trial Design Trial Population Treatment Primary Outcomes

9 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 72 hour, phase 3 study

N=901 Adults aged 18-80 undergoing primary unilateral first metatarsal bunionectomy. Baseline pain rating of 4 the day after surgery.

Tapentadol 50mg, N=275 Tapentadol 75mg, N=278 Oxycodone 10mg, N=279 Placebo, N=69 Study drugs taken every 4-6 hrs for up to 72 hrs Up to 2g paracetamol was allowed as rescue medication.

Sum of pain intensity difference (SPID) over the first 48hrs The results were reported as least squares mean differences from placebo Tapentadol 50mg: 62.4 (95% CI: 39.01-85.73); P<0.001 Tapentadol 75mg: 84.6 (95% CI: 61.29-107.96); P<0.001 Oxycodone 10mg: 81.5 (95% CI: 58.13-104.79); P<0.001 Incidence of treatment-emergent adverse events of nausea & vomiting Tapentadol 50mg: N = 93 (34%); V = 34 (12%) Tapentadol 75mg: N = 127 (46%); V = 77 (28%) Oxycodone 10mg: N = 160 (57%); V = 72 (26%) Placebo: N = 12 (17%); V = 0 (0%)

10 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 10 day, phase 3 study

N=659 Adults aged 18-80 who were candidates for primary joint replacement (knee/hip) surgery due to OA with uncontrolled pain. Baseline pain rating of ≥5 over 3 days before randomisation.

Tapentadol 50mg, N=157 Tapentadol 75mg, N=168 Oxycodone 10mg, N=172 Placebo, N=169 Study drugs taken every 4-6 hrs (maximum of 6 doses/day) for 10 days. Patients allowed to continue with previous stable non-opioid analgesic regimen, no rescue medication permitted.

Sum of pain intensity difference (SPID) over the first 5 days The results were reported as least squares mean differences from placebo Tapentadol 50mg: 101.2 (95% CI: 54.58-147.89); P<0.001 Tapentadol 75mg: 97.5 (95% CI: 51.81-143.26); P<0.001 Oxycodone 10mg: 111.9 (95% CI: 66.49-157.38); P<0.001 Incidence of treatment-emergent adverse events of nausea & vomiting Tapentadol 50mg: N = 29 (18%); V = 11 (7%) Tapentadol 75mg: N = 35 (21%); V = 23 (14%) Oxycodone 10mg: N = 70 (41%); V = 59 (34%) Placebo: N = 9 (5%); V = 7 (4%)


Ref No


11 Randomised, double blind, active controlled, parallel group, multicentre, 90 day, phase 3 study

N=878 Adults aged 18 or older with a clinical diagnosis and at least a 3 month history of lower back pain or OA pain of the knee or hip.

Baseline pain rating of ≥4 before randomisation while taking non-opioid analgesics or 24 hrs after stopping opioid analgesics

Tapentadol 50 or 100mg, N=679 Oxycodone 10 or 15mg, N=170

Study drugs could be taken flexibly every 4-6 hrs as needed (maximum of 6 doses/day) over 90 days. Patients allowed to continue with previous stable non-opioid analgesic regimen, rescue medication – up to 2g paracetamol or 400mg ibuprofen.

Tolerability evaluations Tapentadol Oxycodone Discontinued early: 42% 49% Discontinued due to adverse events: 21% 31% Treatment emergent adverse effects:76.3% 82.9% Nausea: 18.4% 29.4% Vomiting: 16.9% 30% Medication taken for at least 45 days:67% 61% Mean (standard deviation) length of treatment exposure in days: 63 (36.5) 58 (39.9) Mean total daily dose: 284mg 42mg

Tapentadol and oxycodone demonstrated similar efficacy based on pain intensity scores taken throughout the study. Pain improved: 66% 62%

12 Randomised, double blind, active and placebo controlled, parallel group, multicentre, phase 3 study

N=603 Adults aged 18 to 80 with postoperative pain following first metatarsal bunionectomy with osteotomy. Baseline pain moderate to severe; ≥4-point intensity on 11-point numerical rating scale (NRS).

Tapentadol 50mg, N=119 Tapentadol 75mg, N=120 Tapentadol 100mg, N=118 Oxycodone15mg, N=125 Placebo, N=121 Study drugs taken every 4-6 hrs for 72 hrs.

Sum of pain intensity difference (SPID) over the first 48hrs

Tapentadol 50mg: mean 119.1; SD 125.86; p<0.001 vs. placebo Tapentadol 75mg: 139.1 (118.93); p<0.001 vs. placebo Tapentadol 100mg: 167.2 (98.99); p<0.001 vs. placebo Oxycodone 15mg: 172.3 (110.86); p<0.001 vs. placebo Placebo 24.5 (120.93)

≥ 30% reduction in pain intensity at 48 hrs Tapentadol 50mg: 65%; p<0.001 vs. placebo Tapentadol 75mg: 68%; p<0.001 vs. placebo Tapentadol 100mg: 79%; p<0.001 vs. placebo Oxycodone 15mg: 78%; p<0.001 vs. placebo Placebo 40%

Incidence of nausea, vomiting and constipation Tapentadol 50mg & 75mg: 46% Tapentadol 100mg: 59% Oxycodone 15mg: 73%


Ref No


13 Randomised, single dose, double blind, active and placebo controlled, double dummy, multicentre, phase 2 study

N=400 Adults aged 18 or older with postsurgical dental pain. Pain moderate to severe on a visual analogue scale within 6 hours post surgery.

Tapentadol 25mg, 50mg, 75mg, 100mg or 200mg Morphine 60mg Ibuprofen 400mg Placebo Single dose of study drug taken

Mean total pain relief score over 8 hrs after drug administration

Tapentadol 25mg: 6.3 (standard deviation 8.4) vs. placebo Tapentadol 50mg: 7.9 (8.1) vs. placebo Tapentadol 75mg: 9.7 (8.5) vs. placebo; p ≤ 0.05 Tapentadol 100mg: 11.6 (8.2) vs. placebo; p ≤ 0.001 Tapentadol 200mg: 15.3 (7.5) vs. placebo; p ≤ 0.001 Morphine 60mg: 13.8 (10.3) vs. placebo; p ≤ 0.001 Ibuprofen 400mg: 17.9 (9.9) vs. placebo; p ≤ 0.001 Placebo: 4.7 (7.3)

50% pain relief experienced Tapentadol 25mg: 32% Tapentadol 50mg & 75mg: 46% Tapentadol 100mg: 65% Tapentadol 200mg: 88% Morphine 60mg: 65% Ibuprofen 400mg: 77% Placebo: 26%

Incidence of adverse effects lower with all doses of tapentadol vs. morphine 60mg (not statistically significant)

14 Randomised, double blind, placebo controlled, multicentre, phase 2 study

N=269 Adults aged 18 to 65 with postoperative pain following first metatarsal bunionectomy with osteotomy. Pain moderate to severe; ≥4-point intensity on 11-point NRS.

Tapentadol 50mg, N=67 Tapentadol 100mg, N=68 Oxycodone10mg, N=67 Placebo, N=67 Study drugs taken every 4-6 hrs for 72 hrs.

Sum of pain intensity difference (SPID) over 24hrs on day 3

Tapentadol 50mg: mean 33.6; SD 19.7; p=0.0133 vs. placebo Tapentadol 100mg: 29.2 (15.2); p=0.0001 vs. placebo Oxycodone 10mg: 35.7 (17.2); p=0.0365 vs. placebo Placebo 41.9 (17.7)

Nausea: tapentadol = 46.3%; oxycodone = 71.6% Dizziness: 32.8% vs. 17.9% Vomiting: 16.4% vs. 38.8% Constipation: 6% vs. 17.9% Somnolence: 28.4% vs. 26.9%


Appendix 2 – Summary of published and unpublished clinical trials with SR tapentadol

Ref No


15 Randomised, double blind, active and placebo controlled, parallel group, multicentre, 12 week, phase 3 study

N=1030 Adults ≥ 40 years old with a diagnosis of OA of the knee (ACR criteria) requiring analgesics equivalent to ≤160mg oral morphine/day for ≥ 3 months before the study. Pain moderate to severe; ≥5-point intensity on 11-point NRS 3 days before randomisation

Tapentadol 100 to 250mg, N=346 Oxycodone 20 to 50mg, N=345 Placebo, N=339 Adjustable doses taken twice daily for 12 weeks (after a 3 week titration period)

Mean pain intensity change from baseline over 12 weeks The results were reported as least squares mean differences from placebo Tapentadol: -0.7 (95% CI: -1.00, -0.33) Oxycodone: -0.3 (95% CI: -0.67, 0.00) Statistical significance not stated Trial completed by – Tapentadol: 57.3% (197/344) Oxycodone: 35.4% (121/342) Placebo: 61.4% (207/337) Discontinuations were mainly due to due to adverse effects in the tapentadol and oxycodone groups (19.2%, 66/344 and 43%, 147/342 respectively) and lack of efficacy in the placebo group (16.6%, 56/337). Incidence of treatment emergent adverse effects; constipation, nausea & vomiting Tapentadol: 75.9%; 18.9%, 21.5%, 5.2% Oxycodone: 87.4%; 36.8%, 36.5%, 17.8% Placebo: 61.1%; 6.5%, 6.8%, 3.3%

16 Randomized double-blind, placebo and active-controlled, parallel-arm, multicentre, 12 week, phase 3 study

N=987 Adults ≥ 40 years old with a diagnosis of OA of the knee (ACR criteria) requiring analgesics equivalent to ≤160mg oral morphine/day for ≥ 3

Tapentadol 100 to 250mg, N=319 Oxycodone 20 to 50mg, N=331 Placebo, N=337 Adjustable doses taken twice daily for 12 weeks

Mean pain intensity change from baseline over 12 weeks The results are reported as the reduction in daily pain intensity on an 11 point numeric scale Tapentadol: -2.5 (standard deviation 2.18) Oxycodone: -2.1 (2.17) Placebo: -2.2 (2.06) No statistical analysis is provided.


months before the study. Pain moderate to severe; ≥5-point intensity on 11-point NRS 3 days before randomisation

(after a 3 week titration period)

Trial completed by – Tapentadol: 56.1% (179/319) Oxycodone: 35.9% (119/331) Placebo: 63.8% (215/337) Discontinuations were due to adverse effects in the tapentadol and oxycodone groups (18.8%, 60/319 and 40.8%, 135/331 respectively) and lack of efficacy in the placebo group (10.1%, 34/337). Incidence of treatment emergent adverse effects; constipation, nausea & vomiting Tapentadol: 67.1%; 17.55%, 20.38%, 10.03% Oxycodone: 84.9%; 34.44%, 37.16%, 25.98% Placebo: 55.5%; 9.20%, 6.23%, 3.86%

17 Randomized double-blind, placebo and active-controlled, parallel-arm, multicentre, 12 week, phase 3 study

N=981 Adults aged 18 or older with chronic, non-malignant low back pain requiring analgesics equivalent to ≤160mg oral morphine/day for ≥ 3 months before the study. Pain moderate to severe; ≥5-point intensity on 11-point NRS.

Tapentadol 100 to 250mg N=321 Oxycodone 20 to 50mg N=334 Placebo, N=326 Adjustable doses taken twice daily for 12 weeks (after a 3 week titration period)

Mean pain intensity change from baseline over 12 weeks The results were reported as least squares mean differences from placebo Tapentadol: -0.7 (95% CI: -1.06, -0.35), p<0.001 vs. placebo Oxycodone: -0.8 (95% CI: -1.16, -0.46), p<0.001 vs. placebo Trial completed by – Tapentadol: 52.2% (166/318) Oxycodone: 40.5% (133/328) Placebo: 47.6% (152/319) Discontinuations were mainly due to adverse effects in the tapentadol and oxycodone groups (16.7%, 53/318 and 32.3%, 106/328 respectively) and lack of efficacy in the placebo group (20.7%, 66/319). Incidence of treatment emergent adverse effects Tapentadol: 75.5% Oxycodone: 84.8% Placebo: 59.6%


24 Pooled analysis of the 3 above trials

N=3001 Tapentadol 100 to 250mg N=987 Oxycodone 20 to 50mg N=1012 Placebo, N=1002

Mean pain intensity change from baseline over 12 weeks The results were reported as least squares mean differences from placebo Tapentadol: -0.6 (95% CI: -0.80, -0.39), p<0.001 vs. placebo Oxycodone: -0.8 (95% CI: -0.53, -0.12), p=0.002 vs. placebo Discontinuations: total no; due to adverse effects; lack of efficacy Tapentadol: 43.5% (425/978); 18.3% (179/978); 6.2% (61/978) Oxycodone: 61.7% (616/999); 39.4% (394/999); 3.4% (34/999) Placebo: 40.6% (402/991); 6.6% (65/991); 16.4% (163/991) Median time to treatment discontinuation Tapentadol: 118 days Oxycodone: 39 days Placebo: 124 days

18 Randomised, open label, multicentre, 52 week, phase 3 study

N=1121 Adults aged 18 or older with OA pain of the knee or hip or non-malignant low back pain for ≥ 3 months.

Baseline pain rating of ≥4 on 11 point NRS.

Tapentadol 50 to 250mg N=894 Oxycodone 10 to 50mg N=223 Adjustable doses taken twice daily for 51 weeks (after a 1 week titration period)

Safety of tapentadol SR over 1 year

Overall incidence of at least 1 treatment emergent adverse effect Tapentadol: 85.7% Oxycodone: 90.6%

Incidence of constipation, nausea, vomiting Tapentadol: 22.6%, 18.1%, 7% Oxycodone: 38.6%, 33.2%, 13.5% Overall treatment discontinuation Tapentadol: 53% Oxycodone: 65% Reduction in mean pain intensity scores at the end of 52 weeks Tapentadol: -3.22 (standard deviation 2.66) Oxycodone: -3.41 (2.41) The reduction occurred after the first 4 weeks and generally maintained at that level for the next 48 weeks.


Comments received

Dr Mike Bailey, Lead Clinician, Pain Management, Ipswich Hospital

Tapentadol is an interesting drug with opioid and NA re-uptake inhibitory properties. In that respect, it is in a separate class from the other strong opioids. So far it’s unclear as to where it will fit in clinically. I am ambivalent in respect to its introduction. It may well have a role in severe neuropathic pain (failed back surgery syndrome etc) but at the same time its another strong opioid and I am reluctant to use these extensively. As you can see from the press there has been a large increase in prescribing of this class. Certainly in the US there are problems. If we use it, I think it should be on a named patient basis, and I think we should have clear ideas as to who we would recommend it for (similar to Targinact). I wouldn't rush to recommend it as being initiated by any but palliative care or pain clinic at present. 26/09/11 - I have had a chance to discuss this further with my palliative care colleagues. We would request the inclusion of MR tapentadol on the formulary as a Chronic pain or palliative care consultant initiated strong opioid if MR morphine is ineffective. Thus it could be continued in the community if initiated in the Pain Clinic or by the Palliative Care team at the hospital (I cannot speak for the hospice). The lower side effect profile (compared to oxycodone) makes it worth considering, and my impression is that patients with severe mixed or neuropathic pain would be potential candidates for trying this drug as a second-line strong opioid. The SMC sets fairly rigorous standards - I think their decision supports our case. I am not aware of any papers other than the ones which you have quoted. Dr Marcia Schofield, West Suffolk Hospital

These comments refer to the MR product only. The mu opioid receptor agonism is 30x less than morphine. NICE guidance on osteoarthritis suggests that specialist opinion should be sought prior to initiation of strong opioids. The place of tapentadol is after an unsuccessful trial of morphine due to intolerance of side effects or lack of efficacy. In this case, opioid switch is generally undertaken by pain clinicians, with appropriate monitoring. Abuse may occur with all strong opioids. However, due to less agonist activity at the mu receptor, we feel that tapentadol is less likely than oxycodone to represent an attractive drug for supply diversion. The pricing of tapentadol is similar to oxycodone and the SMC data seems to suggest that there is a cost-neutral impact of substituting tapentadol SR for oxycodone SR. We estimate that there are closer to 61,620 people in chronic pain, of which 1,230 are on a step 3 opioid. Only 15% of those patients are taking oxycodone SR (n=185). Pain clinic referrals in West Suffolk in which opioid switch is undertaken represent about 15-20% of our referral (approx 1200 patients per year) which gives a potential figure of 240 patients, most of whom are going to be given a trial of methadone. Hence the potential patient number of those who could be potentially trialled on tapentadol is 75-100 patients per year. I agree with Dr Munglani in the sense that tapentadol is a useful addition to our armentarium. Chronic pain patients referred to pain clinic represent less than 1% of the total population with chronic pain and are universally considered to be the most difficult patients to treat. I do not feel that there will be a significant


‘creep’ into the general population due to the occasional dysphoric effects of tapentadol (similar to buprenorphine) that have been reported by some of our patients. The Lange paper showed significant improvement in quality of life in PRO compared to both placebo and oxycodone MR (SF36 and EQ5D) and patient satisfaction with treatment compare to oxycodone MR (demonstrated by patient global impression of change scores). Tapentadol’s position as a scheduled drug will restrict its use as there s a general reluctance to prescribe strong opioids in primary care in Suffolk and we expect that this will be subject to specialist initiation and GP continuation. From a health economic perspective, work supplied by the manufacturer (HEM) suggests the cost associated with tapentadol use to be £3573 per year yielding a 0.5725 QALY over the course of 1 year. Oxycodone treatment is associated with costs of £3647 per patient and generates a 0.5678 QALY. From a cost-effectiveness perspective, the tapentadol MR is £74 less per patient and generates a greater health gain of 0.0047 QALYs over the 12 month course of the trial. As of the last WSH D+T meeting, it was decided to allow the prescription of tapentadol by the chronic pain team only, for patients with chronic, ongoing pain in whom a trial of appropriate step 3 opioids (MST) was not tolerated. The patients would be initiated and initially monitored by the pain team. It was expected that the PCT would eventually allow the prescription of tapentadol in the group subject to specialist initiation and initial monitoring; as because this is a controlled drug, current regulations require patients to collect their prescriptions in person- This would discriminate against those with disabilities who would find it hard to attend either due to financial cost or transport difficulties. Norfolk & Norwich DTC have approved tapentadol, they are awaiting ratification. Mid Essex APC approved tapentadol for consultant initiation and GP continuation in chronic pain and palliative care. Dr Rajesh Munglani, Consultant in Pain Medicine, West Suffolk Hospital

Thank you for the opportunity to provide a little bit more information on Tapentadol. Firstly I would like to mention my own experience of the drug. I have a lot of patients who basically are intolerant of Morphine and Oxycodone, if anyone needs stronger agents than Co-codamol or Meptazinol, find the Morphine and Oxycodone do not suit them and suffer adversely with side effects. In some of these patients, particularly if they report a useful response to Tramadol, I have found that Tapentadol has been giving them excellent relief and a much better quality of life. I appreciate that this is a small group of patients, however it does suggest a way forward for the use of Tapentadol, which is a failure to respond to agents such as Co-codamol and Tramadol and also a failure to respond to Oxycodone and Morphine. My experience is that it is useful for both neuropathic pain and indeed low back pain in particular, however back surgery does seem to be responsive to it. I think my experience is matched by the evidence in low back pain, particularly for example the paper by Lange which I am sure Gruenenthal would have sent you, Advances Therapeutics 2010. It is clear looking at this paper that the increasing doses of Tapentadol and Oxycodone if monitored over time, those who actually discontinue due to adverse events are much higher in Oxycodone. In Tapentadol 56.5% of patients continue to take the drug, compared to 59.4% in placebo, whilst only 38.3% completed the course with Oxycodone and this is also matched in the long term studies. The pain relief, overall, as you will see in the paper is better than the Oxycodone. The dose of Tapentadol was at about 200mg bd. If one looks at the SF36, one can see that there is a very significant difference between Tapentadol and Oxycodone, particularly in physical functioning, bodily pain and physical role.


Interestingly Oxycodone produces fairly low levels of quality of life in such studies, and this matches my own opinion that one has to be extremely careful with strong opiates as they do not tend to give a good long term quality of life and I published the same in a letter to the BMJ about a year or two ago. I am not a great advocate of large doses of opiates being prescribed in the community. I tend to favour injections and physical therapy i.e. non-pharmacological processes wherever possible. I am also aware that a lot of drugs have very significant adverse side effects and such prescriptions tend to be stopped. My own experience is Tapentadol actually is a significant new addition to our armamentarium. It does seem to be better tolerated i.e. people do not seem to stop the drug so quickly as with others, and does seem to improve quality of life. For a small group of patients who are intolerant of other medication I would ask that we, as Consultants and doctors in the Pain Clinic, be allowed to prescribe it and then the prescription continue in the community. Overall the savings will be in not having to prescribe other drugs, including I suspect anti-neuropathics. Although I have not laboured on the anti-neuropathic effect, I think it is significant and probably equivalent to Tramadol if not better, just from my experience of using it. Dr Jenna Kitchen, St Elizabeth Hospice, Bury St Edmunds

Very comprehensive I have no clinical experience of using Tapentodol yet. A few thoughts: There may be a place for those few who tolerate neither Morphine nor Oxycodone (some develop dysphoria). The lack of serotonergic activity may be an advantage for them. Some pains do not respond to Fentanyl which would be my usual alternative when both morphine and Oxycodone are not tolerated. Dr Rosemary Wade, Consultant in Palliative Medicine, West Suffolk Hospital

Thank you for the opportunity to see your review of Tapentadol. Unlike my chronic pain colleagues, I find that very few palliative care patients are intolerant of opiates when prescribed carefully with appropriate adjuvants. Within the hospital, there are already enough analgesics to confuse the junior doctors but there may well be a place within the community and in chronic pain. It appears there is no experience of prescribing Tapentadol at present but the review looks very comprehensive.


Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications

For many years scientists have recognised two types of research:

Primary: original studies, based on observation or experimentation on subjects.

Secondary: reviews of published research, drawing together the findings of two or more primary studies.

In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this-

Rank: Methodology Description

1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews."

2

Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals)

Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points.

3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.

4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups.

5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time

6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series

7 Expert opinion A consensus of experience from the good and the great.

8 Anecdotal Something a bloke told you after a meeting or in the bar.

Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008


To Decide if a Medication Is To Be Used In Suffolk

Criterion to be measured Tends to poor 2 Medium 4 Tends to good

Quality of evidence in the papers reviewed 7 - 8 5 - 6 3 – 4 2 1

Magnitude of effect inferred from trials reviewed Low x Medium High

Are trial end-points surrogate markers or clinical outcomes? Clinical outcome

Clinical usefulness of trial end-points x

Known Side Effect Profile High Medium Low

Known Interactions High Medium Low

Concern re Possible Side Effects Not Yet Uncovered High Medium Low

Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium x Good

NNT High Medium Low

Comparison Of Effectiveness With Other Medicines In Use For The Same Condition

Poor Medium Good

Severity of Condition to be Treated Trivial Medium Severe

Novel drug or member of existing class Novel

Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration – maximum and minimum uptake)

20%

Is the drug to be used in Suffolk?

Prescriber’s Rating Definitions

Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are “me-too” products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages.

(With acknowledgement to Prescrire)


To Decide Where A Medication Is To Be Used In Suffolk

Criterion Red Amber Green Blue

Skills of the prescriber Experience Of The Condition Specific Specific Specific General

Diagnosis Specific Specific Specific General

Monitoring Progress Of Treatment

Difficult Specific General General

Therapy Patient Selection Difficult Specific Specific Easy

Initiation Of Treatment Difficult Difficult Easy Easy

Dose Titration Difficult Specific Easy Easy

Monitoring Of Side Effects Complex Easy Easy Easy

Method Of Administration Complex Normal Normal Normal

Discontinuation Of Treatment Complex Complex Easy Easy

QIPP Recommendation Green with recommendations that it is used with a strictly defined cohort of patients initiated at WSH Pain Clinic.

References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1 Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2

Documents

Suffolk Drug & Therapeutics Group · 2016-01-13 · buprenorphine (Transtec patches, sublingual tablets) [8] Place in therapy Tapentadol IR has been trialled in post bunionectomy,