NORSPAN Patch Ref.[50647] Active ingredients: Buprenorphine

Pharmacotherapeutic group: Analgesics, opioids
ATC code: N02AE01

Buprenorphine base (active). CAS Registry Number 52485-79-7.

The structural formula is:

Buprenorphine is a white or almost white powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol and ether and slightly soluble in cyclohexane. The pKa is 8.5. The chemical name of buprenorphine is (2S)2[17-(cyclopropylmethyl)-4, 5α-epoxy-3-hydroxy-6-methoxy-6α, 14-ethano-14α-morphinan-7α-yl]-3, 3-dimethylbutan-2-ol. The molecular weight is 467.6 and the empirical formula is C29H41NO4.

Buprenorphine is a µ-opioid agonist, acting at mu-opioid receptors. The opioid agonist activities of buprenorphine are dose related. Buprenorphine also has antagonistic activity at the kappa-opioid receptor. It is classified as a psychotropic substance under international convention.

Like other opioid agonists, buprenorphine produces dose-related analgesia, however, a ceiling effect to analgesia is well documented. Buprenorphine binds to and dissociates from the mu-receptor slowly, which may account for the prolonged duration of analgesia and, in part, for the limited physical dependence potential observed with the medicine.

Buprenorphine produces similar effects to other opioids on the central nervous, cardiovascular, respiratory and gastrointestinal systems, although the intensity and duration of the effects may vary when compared with other opioids. Opioids may also influence the hypothalamic-pituitary-adrenal or – gonadal axes, including an increase in serum prolactin and decreases in plasma cortisol and testosterone, which can manifest in clinicalsymptoms.

Since kappa-receptor agonist activity is related to psychotomimetic and dysphoric effects, buprenorphine is expected to produce fewer psychotomimetic and dysphoric effects than medicines with kappa-agonist activities.

Like other opioid agonists, buprenorphine may produce increases in cerebrospinal fluid pressure, cause altered mentation, mental clouding or amnesia.

Buprenorphine acts to reduce blood pressure in a manner similar to other opioids. NORSPAN patch application resulted in transient decreases in blood pressure in healthy young and elderly subjects, without clinical adverse events.

Like other opioid analgesics, buprenorphine has a potential of respiratory depression. Respiratory depression is less common than with full mu-agonists, such as morphine, and there appears to be a ceiling effect. However, evidence suggests that buprenorphine is a partial agonist with respect to its respiratory depressant activity. When respiratory depression occurs it appears to have a slower onset and longer duration compared with morphine.

Administration of buprenorphine to persons who are physically dependent on full mu-opioid agonists may precipitate an abstinence syndrome depending on the level of physical dependence, and the timing and dose of buprenorphine.

Like other opioids buprenorphine may cause nausea, vomiting, constipation and an increase in biliary tract pressure. Effects on the immune system were seen with natural opioids like morphine in in vitro and animal studies, although the clinical significance of these is unknown. It is not known whether buprenorphine, a semisynthetic opioid, has immunological effects similar to morphine.

Buprenorphine can cause dose-related miosis and urinary retention in some patients.

Clinical Trials

The safety and efficacy of NORSPAN patch in the management of chronic pain has been studied in 10 clinical trials [1,698 patients treated with NORSPAN patch]. The active and placebo-controlled clinical trials included patients with moderate to severe, chronic pain of osteoarthritis, low back and non-cancer pain requiring opioid analgesia. A single trial examined the safety of three doses of NORSPAN patch given for 72 hours to patients following orthopaedic surgery. No trials have been conducted in patients with cancer related pain.

BUPN.CLIN0001 was a randomised, double-blind, double dummy, parallel, equivalence study comparing the efficacy and tolerability of NORSPAN patch 5, 10 and 20mg applied every seven days with sublingual buprenorphine tablets 200 and 400mcg [Temgesic] in 238 patients with moderate to severe pain due to osteoarthritis [hip and/or knee, 85% >one year]. Patients were titrated to optimum pain control over 21 days, and continued at this level for 28 days. Paracetamol was permitted for breakthrough pain and all usage recorded. The primary efficacy variable was pain intensity recorded during the assessment period [Days three and seven, BS-11 scale – see Table 1]. The Per Protocol mean reductions in pain scores ranged from 2.6 to 3.6 across the three daily rating assessments (morning, midday, evening) and the estimated mean difference between both active treatment arms was minimal [range 0.001 to 0.13]. The 95% confidence intervals for the difference between treatments were within the range -1 to 1, compared with the pre-specified equivalence margins of -1.5 to 1.5. This demonstrated equivalent efficacy. At study completion 70% [40/51] of patients on patch and 75% [42/51] on tablets rated their pain relief as good or very good.

Table 1. Pain intensity scores in study BUPN.CLIN0001:

There was no difference in escape medication usage and the incidence of discontinuation due to lack of efficacy was similar between the two treatment groups [9% Temgesic vs 14% NORSPAN patch]. The most common adverse events reported were those commonly associated with the use of opioids (nausea, vomiting, dizziness, somnolence, headache and constipation).

BP98-1201 was a randomised, double-blind trial comparing the efficacy and safety of NORSPAN patches 5, 10 and 20mg, applied every seven days, with hydrocodone/paracetamol [2.5mg/250mg] tablets four times a day (qid) in 270 patients with chronic moderate to severe back pain [pain intensity ≥5 BS-11 scale], not controlled by non-opioid analgesia alone [ibuprofen 400mg qid]. Patients were titrated to optimum pain control over 21 days, and continued at this level for 35 days. The primary efficacy variables were average pain intensity [BS-11 scale*] and patient satisfaction with medication over Days 21-56+, refer Table 2. The Intent to Treat (ITT) population mean baseline pain intensity was 7.74 (NORSPAN patch group) compared with 7.65, which reduced through Days 21-56 to 5.96 and 6.04, respectively. The difference (and 95% confidence interval) in average pain intensity between the two treatments was -0.08 [-0.06 to 0.44]. The difference between the two treatments in patient global satisfaction was 0.16 [-0.08 to 0.39]. NORSPAN patch was equally effective as hydrocodone/paracetamol tablets in relieving pain and for patient satisfaction.

Table 2. Pain intensity scores in study BP98-1201:

^* Pain intensity was assessed by the BS-11 pain scale, an 11-point scale for rating current pain, where 0 = “no pain” and 10 = “pain as bad as you can imagine”.
⁺ Patient global satisfaction with medication was assessed on a 4-point scale, with the question “Rate the study medication you received for pain”.

The majority of adverse events reported were mild or moderate in severity and were typically associated with opioid therapy. Withdrawals due to lack of efficacy was similar for both groups (15% for NORSPAN patch and 14% for hydrocodone/paracetamol). No changes in laboratory values were considered related to treatment, and no clinically important changes were reported for pulse rate, respiratory rate or physical examinations.