06/2012

Tapentadol ( Palexia®) for chronicintense painProlonged release opioid of unknown therapeutic value

Indications1

Management of chronic severe pain in adultsthat can only be treated with an opioid.

Mechanism of action and pharmacokinetics1

Potent analgesic opioid, with a bioavailabilityof 32% and maximum concentration between3-6 hours. It is metabolized fundamentally byconjugation and none of its metabolites pres-ent analgesic propertites. Elimination is renal(half-life = 4 hours).

� Tapentadol has proved more effective thanplacebo in arthrosis, lumbalgia and painrelated to diabetic neuropathy.

� However, the results should be interpretedwith caution as there are important limita-tions.

� No direct comparisons have been madewith other opioids. There is only one analy-sis in which tapentadol did not show anydifferences when compared to oxycodone.

� No studies are available on its use for painin cancer patients.

� This drug has the same adverse effectprofile as other opioid analgesics. Themost frequent are nausea, constipation,dizzyness, somnolence and cefalea.

� There are no rapid release presentations.

The qualification assigned to the drug was agreed by the Drug Assessment Committees of Andalusia, Basque Country, Catalonia Institute of Health, Aragonand Navarre. The current report is based on the available information and is susceptible to be updated according to the latest evidence. Let us remind the re-ader about the importance of notifying the Pharmacovigilance Centre when there are suspicions of adverse reactions to drugs.

When a major opioideis required, thenmorphine is theelective choice

*www.dtb.navarra.es

Posology and methods of administration1

The tablets should be taken entirely, andshould not be masticated or triturated. Thedrug can be taken with or without food.

Treatment onset: in patients taking opioids,50 mg twice daily is the recommeded startingdose. Patients with previous treatment withopioids may require higher initial doses1. Thedose equivalence of tapentadol:morphine is2.5:1 and tapentadol:oxycodone is 5:1.

Dose adjustments: should be done in incre-ments of 50 mg every 12 hours every 3 daysuntil adequate pain control is achieved. Max-imum daily dose: 500 mg.

*Note: costs calculated with the approximate equipotent doses of available presentations accordingto conversion factors2.

INFORMATION:Servicio de Prestaciones Farmacéuticas Plaza de la Paz s/n, 4ª planta - 31002 Pamplona T 848429047 F 848429010

NEW DRUGS ASSESSMENT COMMITTEE:Iñaki Abad, Mª José Ariz, Ana Azparren, Mª Concepción Celaya, Juan Erviti, Javier Garjón, Javier Gorricho, Antonio López, RodolfoMontoya, Mikel Moreno, Lourdes Muruzábal

Suspending treatment: reduce doses grad-ually to avoid abstinence-related symptoms.

Clinical efficacy

There are no studies directly comparing tapen-tadol to other major opioids. The EMA assess-ment report3 included two studies on kneearthrosis4 (of which one study remains unpub-lished), one study on lumbalgia, another on di-abetic neuropathy and one study on long termtolerance7. A pooled data analysis8 has alsobeen published which includes individual da-ta of the patients in two published4,5 studiesand of those in the unpublished study.

With respect to knee arthrosis and lumbalgia,tapentadol was compared to placebo and oxy-codone as the active comparator (studies werenot designed for a direct comparison). After awashout phase and dose adjustments (3weeks), the maintenance period of treatmentlasted 12 weeks. The patients included showedan average score measuring pain intensity atthe start of the study of ≥5 points on a scale of11 points (from “0” = no pain to “10” = worstpain imaginable). The doses employed oftapentadol were 100-250 mg every 12 hourscompared to oxycodone 20-50 mg every 12hours. Both tapentadol and oxycodone provedsignificantly superior to placebo. The differ-ences for tapentadol were -0.7 (95%CI, -1.00to -0.33)4 and -0.7 (95%CI, -1.06 to -0.35)5

while those for oxycodone were -0.3 (95%CI,-0.67 to -0.00)4 and -0.8 (95%CI, -1.16 to -0.46)5. However in the unpublished study thedifferences between tapentadol and placebodid not show significant differences3. Only oneof these studies reports the difference in theaverage intensity of pain with respect to thebaseline scores in each treatment group: -2.8(tapentadol), -2.9 (oxycodone), and -2.1 (place-bo)5. These data should be interpreted with pre-caution as the rates of patients abandoningtreatment were very high and unbalanced:placebo (range 39-52%), tapentadol (range 43-48%), oxycodone (range 60-65%). As a resultthis limits the internal validity of the outcomes.

In the study on patients with peripheral dia-betes related neuropathy6 the efficacy oftapentadol was compared to placebo for 12weeks, after an initial phase lasting 3 weeks toallow for tapentadol dose titration. Tapentadolproved superior to placebo in the average re-duction of pain intensity -1.3 (95%CI, -1.70 to-0.91). In patients treated with tapentadol therewas no change in the average intensity of painwith respect to baseline values. However,those treated with placebo showed an in-crease in the intensity of pain of +1.4 points.The rate of withdrawals was 32% in bothgroups, which could limit the results of thestudy. In the pooled data study8, tapentadoldid not show any differences compared to oxy-codone.

SafetyAdverse reactions1

Similar to the rest of the opioids. Most frequentadverse effects (≥10%): nausea, constipation,dizzyness, somnolence, and cefalea.

Contraindications1

Hypersensitivity to the drug or any of its ex-cipients (contains lactose), important respi-ratory depression, acute or severe bronchialasthma, hypercapnea, paralytic ileum, and se-vere liver or renal failure.

Warnings and precautions1

Potential for abuse and addiction and absti-nence syndrome. Precaution is necessary incases of respiratory dysfunction, head injuryand raised intracraneal pressure, history ofconvulsions and disorders that can increasethe risk of convulsions, moderate liver failureand pancreatic or biliary-tract disease.

Use in special situations1

Pregnancy: use only if the possible benefitsjustify the potencial risk to the fetus (class C)2

Birth: it is not recommended during and im-mediately after delivery. Lactation, childrenand adolescents: its use is not recommend-ed. Liver failure: no dose adjustments are re-quired in mild liver failure, although adjust-ments are necessary in moderate cases. It isnot recomended in severe liver failure. Renalfailure: no dose adjustments are required inmild or moderate renal failure. It is not recom-mended in cases of severe renal failure. El-derly: assess for possible renal and/or liverdysfunction.

Effects on driving capabilities and use of machinery1

Tapentadol can reduce the mental and phys-ical capacities to carry out potentially danger-ous tasks and therefore patients should becautioned.

Interactions1

Its use with MAO inhibitors is contraindicat-ed. Precaution should be taken when usingbenzodiazepines, barbiturics, antipsychoticagents, H1 antagonists, opioids and alcoholgiven the possible increase of the risk of res-piratory depression. The concommitant useof SRSI drugs can provoke a serotoninergicsyndrome. The analgesic effect can be re-duced when employing pentazocine, nal-buphine, or buprenorphine. If treatment withrifampicine, phenobarbital, or Saint Johnswort is initiated or suspended then a reduc-tion in the efficacy or a greater risk of adverseeffects could occur respectively.

Place in therapeutics

With regard to cancer related chronic pain,morphine is the elective choice. However, innon-cancer related chronic pain the use of opi-oids is considered as a second or third line op-tion, as the harm- benefit balance remains un-certain unlike the case of cancer related pain.Before initiating a chronic treatment with opi-oids, in the case on non-cancer related pain acareful evaluation of the patient should be car-ried out and the risk of abuse or dependenceshould be considered10.

There are no randomized clinical trials that di-rectly compare tapentadol with either othermajor opioids (morphine, fentanyl and oxy-codone) or tramadol in the management of pe-ripheral diabetic neuropathy. The analgesic ef-fect of tapendatol has been studied in rareclinical situations compared to placebo. In oth-er trials, both tapentadol and oxycodone haveproved more effective than placebo in themanagement of moderate to severe pain inarthrosis, chronic lumbalgia and peripheral di-abetic neuropathy. The duration of these stud-ies (12 weeks) is very short to adequately eval-uate chronic pain and the exclusion criteriawere highly restrictive. Therefore, the select-ed population for these studies does not ad-equately represent the profile of patients sus-ceptible to benefit from this treatment. Therates of withdrawals due to any cause (includ-ing adverse effects) in all arms of treatmentwere also considerably high and the clinicalrelevance of the benefits was limited. Of thestudies carried out, it is inferred that tapenda-tol presents a similar adverse effect profile toother major opioids, as well as similar risksof abuse and dependence.

The absence of direct comparative studieswith other standard opioids and the limited in-ternal validity of the results from the availablestudies does not offer sufficient or conclusiveinformation with regard to tapentadol’s levelof contribution in terms of efficacy and safe-ty in the management of chronic pain.

Presentations

Palexia retard® (Grünenthal Pharma S.A.) (50,100, 150, 200, 250) mg 60 sublingual tablets(44.02; 88.05; 132.07; 153.33; 169.17) € re-spectively. Requires medical and narcotic pre-scription.

References

A complete report on tapentadol can be foundat: http://www.dtb.navarra.es