Utprøving av nytt smertestillende preparat i mennesker

[Den følgende teksten er et eksempel eller "case", som kan tjene som utgangspunkt for refleksjon og diskusjon. Noen eksempler kan være basert på reelle hendelser, mens andre er fiksjonelle fremstillinger.]

Et legemiddelfirma har utviklet en ny formulering av et sterkt smertestillende preparat i morfingruppen. Denne formuleringen gjør at man kan dosere preparatet to ganger om dagen, noe som ikke var mulig med denne substansen tidligere. Hensikten er å bruke preparatet ved kronisk smerte, enten ved kreft eller ved langvarig smerte som ikke er relatert til kreft. Det er behov for forskjellige substanser med sterk smertelindrende virkning idet pasienter reagerer forskjellig på preparatene. Et tydelig særpreg ved smertebehandling med morfinlignende substanser er at det er veldig stor variasjon i dosebehovet fra pasient til pasient. Dosene blir derfor titrert til man finner en god balanse mellom virkning og bivirkning. Under denne opptrappingsperioden har pasienten alltid tilgang på ekstra smertemedisin (rescue medisin) for å kunne kontrollere smertene. Men før man starter behandling med morfin analgetika eller opioider, har man vanligvis prøvd ut svakere smertestillende tabletter som Paracetamol eller ikke-steroide, antiinflammatoriske midler (NSAIDS), ofte i kombinasjon med f. eks. kodein. Hos pasienter som lider av sykdommer som artrose (slitasjegikt), vil man vanligvis fortsette behandlingen med disse når man bruker morfinanalgetika. Det vil også gjelde for en rekke kreftpasienter og ryggpasienter.

En forskergruppe bestemte seg for å gjøre en systematisk review av dokumentasjonen for det nye preparatet. Man fant ni artikler hvorav tre ble ekskludert pga. lav studiekvalitet, igjen stod seks randomiserte, kontrollerte studier som hadde inkludert i alt 1500 pasienter, de fleste med kronisk smerte uten kreft, alle voksne og samtykkekompetente. Alle studiene var støttet av det farmasøytiske firmaet som hadde utviklet preparatet. I tabellen (PDF-fil) er det informasjon om design, studiedeltakere, intervensjon og funn. Drøft forskningsetiske problemer knyttet til informasjonen i oversikten under. 
Du kan også laste ned oversikten som tabell.

Forklaringer av forkortelser i oversikten
VAS: Visual analog sale, ATC: around the clock therapy, CLBP: chronic low back pain, OA: osteoarthritis, DB: double blind . 24 h doses are reported, administered bid. The # of patients discontinued is during double blind treatment.Sample estimation refers to total number

Studie 1
Design: Randomized, double blind, placebo/active-control, parallel-group study.
Deltagere: Adult patients with chronic OA pain. Must have taken NSAID or opioid for at least 75 to 90 days before screening and had a suboptimal response to these agents. Sample estimation: 240 491 patients randomized 467 ITT analysis 269 completed the study 46/222 discontinued were placebo
Intervensjon: 1 week wash-out period, then 4 weeks treatment of morfoid 40 mg (group 1), or 80 mg (group2); 40 mg for 2 weeks then 80 mg next 2 weeks, or oxoid 40 mg (group 3), or placebo (group 4). Rescue medication not permitted.
Funn: Pain intensity scores and the difference in VAS scores from baseline to the final visit were improved by 62.8% and 70.9% for 40 and 50 mg morfoid, respectively. Most AEs were mild to moderate and related to the opioids, but more AEs occurred in the morfoid groups. Almost 50% of patients receiving active treatment withdrew early, mostly due to non serious AE. Opioid naïve patients accounted for most withdrawals in morfoid groups. Almost 40% of placebos withdrew mainly due to lack of effect.

Studie 2
Design: Randomized, double blind, placebo-controlled, parallel-group phase III study.
Deltagere: Adult patients with chronic OA of the hip or knee. Must have regularly taken NSAIDs with suboptimal response or opioid for 90 days before screening. Sample estimation :240 370 patients randomized 357 ITT analysis 198 completed the study 26/172 discontinued were placebos
Intervensjon: 2-7 day wash out period, then 2 weeks treatment with morfoid 20 mg (group 1), morfoid 80 mg (group 2); 40 mg in week 1 followed by 80 mg in week 2, morfoid 100 mg (group 3); 40 mg week 1, followed by 100 mg in week 2, or placebo (group 4). Rescue medication not permitted.
Funn: Almost 40 % withdrew during the titration phase, most commonly due to adverse effects. A significant difference in pain intensity was shown in favour of morfoid. Majority AEs were mild to moderate and opioid-related. Withdrawals due to lack of effect was nearly 3-fold higher in the placebo than in morfoid 40 and 50 mg. Withdrawals due to AEs occurred in 25.%, 558%, 52%, and 10 % for groups 1, 2, 3, and 4 respectively. Opioid naïve patients had most withdrawals in the morfoid groups

Studie 3
Design: Randomized, multi centre, double-blind, parallel group placebo-controlled study
Deltagere: Adult CLBP patients opioid-naive with moderate to severe CLBP with initial pain intensity score of ≥ 50 mm on VAS, who have taken less than 5mg/day of oxoid or equivalent for the last 2 weeks before screening, presented daily several hrs/day for ≥ 3 months. Sample estimation :160 205 patients randomized 118 completed the study 53/87 discontinued were placebo
Intervensjon: Current pain medication terminated before screening, then 4 weeks morfoid titration period Only responders were randomized to treatment for 12-weeks with morfoid or placebo. Rescue medication permitted (restricted to twice a day.
Funn: Current pain medication terminated before screening, then 4 weeks morfoid titration period Only responders were randomized to treatment for 12-weeks with morfoid or placebo. Rescue medication permitted (restricted to twice a day.

Studie 4
Design: Randomized, double blind, placebo-active-controlled parallel-group study
Deltagere: Adult patients with CLBP that had to be present at least 15 days/month and several hrs/day for at least the past 2 months. Patients had to be treated with stable dose of opioids for at least 3 consecutive days before screening. Sample estimation:195 330 patients randomized in DB titration phase 235 received study treatments 213 ITT analysis, 139 completed the study 53/96 discontinued were placebos
Intervensjon: 1-2 weeks titration period, then morfoid) titrated (20-220mg) or oxoid titrated (40-440 mg), or placebo for18 days. Rescue medication permitted (restricted to twice a day).
Funn: Almost 30 % withdrew during the titration phase, most commonly due to adverse effects. Pain control with oxoid and morfoid was superior to placebo. Placebo was 8-fold more likely to discontinue than morfoid. More constipation and sedation was reported in the opioid treated patients. Equi-analgesic ratio of morfoid (80 mg) to oxoid (155 mg) was 1:2.

Studie 5
Design: Randomized, double blind, placebo-controlled parallel-group study
Deltagere: Adult opioid-experienced ppatients with moderate to severe CLBP which had been present for at least several hours each day for a minimum of 3 months and required to have been receiving stable ATC opioid pain medication equivalent to at least 60 mg/d of oral morphine for the 2 weeks before screening. . Sample estimation :120 143 patients randomized 142 ITT analysis, 67 completed the study 55/76 discontinued were placebos
Intervensjon: Patients converted from their pre study opioids to an equi-analgesic dose of morfoid (bid) then titrated and stabilized within a month, then randomized to morfoid or placebo for 12 weeks. Rescue medication permitted (restrictedto twice a day.
Funn: About 40 % withdrew during the titration phase, most commonly due to adverse effects. Patients in the morfoid group maintained effective analgesia throughout the study period, while pain increased significantly in the placebo group. Placebo patients were approximately 8-fold more likely than morfoid ER patients to discontinue because of lack of efficacy. Discontinuation as result of adverse events was similar between groups. morfoid dose at and of titration were 87.2 mg; and 81.7 or 77.8 mg for those who did or did not complete 12 week period, respectively.

Studie 6
Design: Randomized, double blind, crossover study
Deltagere: Adult patients with moderate to severe chronic cancer pain that required long-term outpatient treatment with opioid analgesics. Patients with radiotherapy the two last weeks were excluded. . NO Sample estimation : 45 patients randomized 42 included in ITT analysis -40 completed the study- 3 patients discontinued in period 1, 2 in period 2
Intervensjon: Open-label titration /stabilization phase of morfoid IR or oxoid 3-10 d (both bid). Then randomized to morfoid (10-40 mg) or oxoid CR (20-80 mg) 10 d, and then crossed over to the alternative treatment for 7-10 d. Rescue medication permitted.
Funn: The mean average daily pain intensity ratings of morfoid and oxoid were clinically indistinguishable. Low use of rescue medication in both groups. Most AEs were mild to moderate and related to opioids. Equi-analgesic dose ratio of morfoid (45.9 mg) to oxoid (91.9 mg) was 1:2.

Les om legemiddelutprøving i Forskningsetisk bibliotek (FBIB).