Opioid-induced respiratory effects: new data on buprenorphine

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1 Palliative Medicine 2006; 20: s3-s8 Opioid-induced respiratory effects: new data on buprenorphine Albert Dahan Department of Anesthesiology, Leiden University Medical Center, Leiden When selecting the appropriate long-acting opioid to treat cancer pain, both analgesic efficacy and safety need consideration. Generally, opioids are well tolerated. However, of opioid-typical adverse events, respiraton/ depression is especially important because of the risk of a fatal outcome. Although all potent opio)d analgesics act via the ^-opioid receptor system, they differ in how they affect respirator/ control. Recently, the respiratory effects of fentanyl (1-7 iig/kg) and buprenorphine (0.7-9 iig g/kg) were compared in healthy opioidnatve volunteers. Fentanyl produced dose-dependent depression of respiration with apnoea at doses >3 ^g/kg, while buprenorphine caused depression that levelled at -5 0% of baseline with doses >2 lag/kg. These findings indicate the occurrence of a ceiling in the respiratory depression induced by buprenorphine but not by fentanyl. Surprisingly few studies have addressed the clinically important ability to reverse the respiratory effects of opioids. A recent assessment of the naloxone dose required to reverse 0.2 mg intravenous buprenorphine-induced respiratory depression in healthy opioid-natve volunteers, found that the accumulated naloxone dose causing 50% reversal of respiratory depression was 1.20 ± 0.32 mg/70 kg (given in 30 min); 80% reversal was observed at mg/70 kg (given in 30 min). At greater buprenorphine doses, full reversal is observed when the duration of naloxone infusion is increased. These findings indicate the need for a continuous rather than bolus administration of naloxone to reverse the respiratory effects of buprenorphine. In conclusion, buprenorphine is more favourable compared with fentanyl in respect to ventilatory control. Buprenorphine causes limited respiratory depression with a ceiling effect at higher doses, while fentanyl causes dose-dependent respiratory depression with apnoea at high dose levels. In the rare instance of respiratory depression, reversal is possible with a sufficient and continuous infusion of naloxone. Palliative Medicine 2006; 20: s3-s8 Key words: apnoea; buprenorphine; ceiling effect; fentanyl; naloxone; opioid; respiratory depression Introduction that the desired (antinociceptive) and undesired (respiratory depression) ettects of morphine (and its active Long-acting opioids are important analgesics for the metabohte morphine-6-giucuronide) and probably al! \itreatment of cancer pain but are variable in terms of opioids are linked to the same target: the ^-opioid analgesic efficacy and safety. Ahhough opioids are receptor gene (Oprm).^-^ Mice with intact M-opioid generally well tolerated, consideration of safety is needed receptors showed a dose-dependent decrease in both because - in addition to analgesia - morphine and most breathing frequency and tidal volume. However, no such other opioids produce their characteristic responses both effect was observed in mice lacking the la-opioid receptor centrally and peripherally.'""^ Of opioid-typical adverse (so-called n-opioid receptor knockout mice). Similarly, events, respiratory depression is the most serious because mice with ji-receptors showed dose-dependent antinociof the risk of a fatal outcome for the patient. The ception from morphine, while no effect was observed in mechanism of opioid-induced respiratory depression is j.- ji-opioid receptor knockout mice (see also Figure l).'*'^ opioid receptor inhibition of the brainstem respiratory Clinical studies in volunteers and patients on the control centres. Opioids affect both the rate and depth of effect of morphine on respiration have also shown a respiration, eventually resulting in an increased arterial dose-response relationship.^ ^ For example, morphine partial pressure of carbon dioxide and reduced partial causes a dose-dependent decrease in minute ventilation of pressure of oxygen.^ Data from studies in mice indicate 6-7L/min before the drug is given to unstable and cyclic breathing with both a reduction in the breathing Address for correspondence: Albert Daham Department of ^ Anesthesiology, Leiden University Medical Center P5-Q, P.O.., ^^j ^he depth of breathing at mg/kg.^,, i Box 9600, 2300 RC Leiden, The Netherlands. At higher doses apnoea may occur when morphine is a.dahan@lumc.nl given to persons without pain Edward Arnold (PubUshers) Ltd / pml 126oa

2 s4 A. Dahan Pain assay intact' 22 n 20 -.S 18 E 1.16 Ventilation - CO2 response intact O ^-Opioid Receptor KO Dose ip mg/kg % CO. 7.5 Figure 1 Effect of various doses of morphine on antinociception (left: the tail immgrsion test) and respiration (right: ventilatory response to various concentrations of carbon dioxide} in a mouse with an intact n-opioid receptor gene {intact} and a i-opioid receptor gene knockout mouse. Note the absence of opioid effect in the knockout mice indicating that the receptor gene is the primary site of respiratory and antinociceptive action of opioids. In this short review I will discuss the respiratory behaviour of an opioid that is frequently used in the treatment of pain, buprenorphine. It is a potent opioid with special characteristics. I will (i) compare buprenorphine and fentanyl dose-(respiratory) response curves: (ii) compare buprenorphinc's analgesic and respiratory responses; and (iii) discuss the ability of naloxone to reverse buprenorphine-induced respiratory depression. Respiratory depression: buprenorphine versus fentanyl Recent data from published case studies have indicated a number of instances where patients have suffered severe respiratory depression after the continuous infusion of fentanyl via a transdermal patch."^ " To underline the importance of this issue, of six case patients who presented with drug-induced respiratory depression, two died.^ We relate these serious adverse events to (1) the relatively high doses of fentanyl given; (2) the periodic nature of pain; (3) psychomimetic comedication (such as sedatives, alcohol, other pain medication) and (3) the absence of supervision of the patients. But do all opioids behave in the same way? Our group attempted to answer this question by investigating the comparative etfects on respiratory depression of the equipotent analgesics fentanyl and buprenorphine in rats.'' Fentanyl injected intravenously into animals up to a dosage of 0.09 mg/kg showed a dose-dependent linear increase in arterial pressure of carbon dioxide, a surrogate measure of respiration (Figure 2). On increasing the fentanyl dosage further, the animals died of fatal respiratory depression. In contrast, when buprenorphine was administered intravenously there was an initial increase in arterial pressure of carbon dioxide, which rapidly levelled off even on increasing the dosage up to 3.0 mg/kg (Figure 2). This phenomenon, known as the ceiling effect, represents the point where the agonistic effects of buprenorphine plateau and the drug develops an action more akin to that of an antagonist, thereby limiting respiratory depression.'^''" How do buprenorphine and fentanyl compare in respect to respiratory depression in humans? We conducted a double-blinded, placebo-controlled study of iv dose (mg/kg) Figure 2 Effect of increasing doses of fentanyl and buprenorphine on arterial PCO? in rats. Note the linear increase in CO? after fentanyi but iittle to no increase after buprenorphine. Values are mean±sem, Data are adapted from Dahan etai}^

3 Opioid-induced respiratory effects and buprenorphine s Fentanyi 25 n Buprenorphine f 15 H 15 M PLATEAU 5 - APNOEA Fentanyl dose ()ig/kg) Buprenorphine dose (^g/kg) Figure 3 Effect of increasing doses of fentanyl and buprenorphine on respiration in human volunteers (n^5-8 per dose group; n^i for the highest fentanyl dose). Note the dose-dependent decrease for both drugs with apnoea at high-dose fentanyl but a ceiling or piateau at intermediate to high dose buprenorphine. Values are population mean. For clarity no error bars are shown. Data are adapted from Dahan et al. T2 fentanyl and buprenorphine in 48 volunteers. Using the computer-steered 'dynamic end-tidal forcing" technique, respiratory studies were performed at a clamped endtidal oxygen (15 kpa) and carbon dioxide (7 kpa) tension. Ventilation was measured for up to 7 hours. Doseresponse relationships were observed with fentanyl in the range of 0-9 lig/kg and for buprenorphine at 0-7 ig/ kg (with respect to analgesia fentanyl and buprenorphine are equipotent relative to morphine). Fentanyl caused dose-dependent reduction of minute ventilation with respiratory instability at doses of 3 (ig/kg and greater. In one subject, prolonged periods of apnoea were observed at the highest dose tested (500 ig in a 70 kg volunteer). Buprenorphine similarly caused dose-dependent reduction of minute ventilation, however, in contrast to fentanyl a plateau in respiratory depression (about 50% of baseline) occurred at dosages >3 ig/kg (see also Figure 3). Importantly, no respiratory instability, periodic breathing or apnoea occurred, even at the highest dose tested (600 p,g in a 70 kg volunteer). Buprenorphine: ceiling in respiration but not in analgesia An important question is whether the ceiling in respiratory depression is linked to a concomitant reduction in analgesia. This question was investigated using a standard electric pain model'^ with two groups of patients, each receiving a different dosage of buprenorphine (3 and 6 ng/kg).'^ The results demonstrated that doubling the Breathing 70 Pain reiief Time (hours) Time (hours) Figure 4 Effect of two doses of buprenorphine (3 pg/kg cyan dots; 6 ng/kg grey dots) on respiration (left) and analgesia (right) in human volunteers (n ^ 10 per dose group}. Note that doubling the dose had no further effect on respiration while analgesic efficacy increased significantly. For clarity no error bars are shown. Data are adapted from Dahan ef s/.^^

4 s6 A. Dahan ro mg naloxone Figure 5 Influence of naloxone on buprenorphine-induced respiratory depression. Examples of four volunteers that received 0.2 mg buprenorphine intravenously from t = 2 to t=62 min, followed by various doses of naloxone from t^32 to f ^62 min. Note that at low doses of naloxone (0.5 and 1,0 mg} no reversal occurs while at doses of 2 mg and greater full reversal is observed. Each dot represents a 1-min average. The broken line is baseline ventilation ( -predrug ventilation). The thick black lines are the infusion periods of buprenorphine and naloxone. dosage of buprenorphine from 3 to 6 ^g/kg had no effect on breathing (Figure 4). In contrast, doubling the dosage now had a significant effect as analgesia increased three-fold (Figure 4). This underlines the ability of buprenorphine to instigate a ceiling effect to counter respiratory depression that is independent of its effect on analgesia.'^ Note that this conclusion is valid only for the dose-range tested.'^ Reversal of buprenorphine-induced respiratory depression using naloxone Knowledge of the ability to reverse opioid-induced respiratory depression is important for all potent and clinically used opioids (eg, fentanyl, morphine, buprenorphine). However, there are surprisingly few studies that have addressed the reversal of opioid-induced respiratory effects. Despite data from early studies to the contrary,"^''^ we performed a study investigating the reversal of the effects of buprenorphine on respiratory function with naloxone in humans."'* An adaptive trial design was used to find the dose that caused full reversal of buprenorphine-induced respiratory depression. Twenty-one opioid-naive volunteers were tested over a 90-min period with end-tidal carbon dioxide tension clamped at 7 kpa. Buprenorphine 0.2 mg/kg was administered as a continuous intravenous infusion for 1 hour. After a period of 30 min from the start of buprenorphine infusion, either placebo (NaCI 0.9%, n^t) or naloxone (0.5-5 mg, rt^l4) was infused for 30 min, and the effect on breathing assessed for a further 30-min period afterwards. As expected, placebo did not affect the buprenorphine-induced decrease in ventilation rate during the period 0-60 min. A slow decline in ventilation rate was observed, reaching a nadir of depression after 70 min. On infusing low-dose naloxone (0.5 mg) over 30 min there was little discernible effect on buprenorphine-induced respiratory depression following initial naloxone injection, leading to a continued depression (Figure 5). At such a low dose it is relatively ditticult

5 Opioid-induced respiratory effects and buprenorphine s7 for naloxone to displace buprenorphine already bound to p-opioid receptors.'** However, on increasing the dosage of naloxone to 2 mg, a full reversal of the respiratory effect was observed, returning ventilation to its baseline level (Figure 5). Thus, total reversal of respiratory depression induced by buprenorphine can be brought about at a relatively low dose of continuously infused naloxone. The data show that full reversal of respiratory depression produced by buprenorphine can be achieved by using a continuous infusion of sufficiently high dosages of naloxone. The dose-dependent reversal of buprenorphine-induced respiratory effects follows a sigmoidal relationship (Figure 6): 50% reversal of depression is achieved after 30 min of continuous infusion of naloxone 1.2±O.32mg/7Okg, and 80% reversal with mg/70 kg. Reversal of greater doses of buprenorphine was recently studied in our laboratory (Dahan, unpublished observation) and not surprisingly - we observed that not greater doses of naloxone are needed for reversal but a longer infusion duration is needed. In this respect buprenorphine behaves similar to other potent and long-acting opioids with high altinity at the receptor."' < UJ s a: 1.0 -^ ^ / 1 o # 8 o o Naloxone dose (mg per 70 kg) Figure 6 Effect of various doses of naloxone on reversal of 0,2 mg buprenorphine-induced respiratory depression in human volunteers. The line through the data is the data fit using a sigmoid Emax model. As the Emax =1, full reversal is possible. In gray the naloxone ED50 (50% reversal) and EDso (80% reversal) are given. Data are adapted from Dahan et a/.^^ Note that naloxone doses between 2 and 4 mg will cause full reversal of respiratory depression. Conclusions In summary, buprenorphine compares favourably with fentanyl in respect to ventilatory control. Unlike fentanyl, which causes dose-dependent depression with apnoea at high dosage, buprenorphine causes limited respiratory depression with a ceiling effect at high dosages. In the rare instance of respiratory depression with buprenorphine, full reversal using a continuous infusion of naloxone to obtain a constant (and sufficient) plasma concentration is possible. Acknowledgements The author thanks Grunenthal GmbH. Aachen, Germany for their support and educational grants enabling the studies on buprenorphine. References 1 Martin WR. Pharmacology of opioids. Pharmacol Rev 1983; 35: Budd K, Shipton EA. Acute pain, the immune system and opiommunosuppression. Aviilc Pain 2004; 6; Smith HS. Drugs for pain. Hanley & Belfus Inc, Dahan A, Sarton E, Teppema L. et al. Anesthetic potency and influence of morphine and sevoflurane on respiration in fi-opioid receptor knockout mice. Anesihesiology 2001; 94: Romberg R, Sarton E, Teppema L. ct al. Comparison of morphinc-6-glucuronidc and morphine on respiratory depressant and antinociceptive responses in wild type and (j-opioid receptor deficient mice. Br J Anaesth 2003; 91; Jacobson L, Chabal C, Brody MC. A dose-response study of intrathecal morphine; efficacy, duration, optimal dose, and side eftects. Anesih Analg 1988; 67; Bailey PL, Rhondeau S, Schafer PG, el at. Doseresponse pharmacology of intrathecal morphine in human volunteers. Anesihesiology 1993; 79: 49-59; discussion 25A. 8 Dahan A, Romberg R, Teppema L, el al. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesihesiology 2004; 101; Regnard C, Pelham A. Severe respiratory depression and sedation with transdermal fentanyl; four case studies. Palliat Med 2003; 17; WHO Drug Information. 2004; 18; Canadian Adverse Reaction Newsletter 2004; Dahan A, Yassen A, BijI H. el al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Amiesih 2005; 94;

6 s8 A. Dahan 13 Sporer KA. Buprenorphine: a primer for emergency 19 Bowdle TA. Pharmacology of analgesia. In Healy TEJ, physicians. Ann Emerg Med 2004; 43: Knight PR eds, Wylie and Churchill-Davidson's a practice 14 Walsh SL, Preston KL, Stitzer ML, et al. Clinical o/«he5//ies/a, seventh edition. Arnold, 2003: pharmacology of buprenorphine: ceiling eftect at high 20 Bijl H. Yassen A, Olofsen E. c-i at. Full reversal of doses. Clin Pharmacol Ther 1994; 65: buprenorphine-induced 15 Sarton E, Olofsen E, Romberg R. et al. Sex differences in respiratory depression by the opioid receptor antagonist morphine analgesia: an experimental study in healthy naloxone. Ned Tijd.schr r Anesth (Neth J Aneslh) 2006: volunteers. Anesthesiology 2000; 93: ^^ nrca^ 16 Dahan A, Yassen A. Romberg R, et al. Buprenorphine 2I Takahashi M. Sugiyama K. Hori M, Chiba S, Kusaka K. induces ceiung m respiratory depression but not m Naloxone reversal of opioid anesthesia: clinical evaluaanalgesia. Br J Anaesth 2005; ^-^^ ^^^ pl^^^^ concentrations of continuous naloxone???-, p"^''r''^^?nm"t.?f'^''.''.fr "'"'' i"f""^ion ^f^e-- anesthesia with high-dose fentanyl. J fnt J Clm Pract Suppl 20(i?i: m. 3^-^., 2^-24..,.,,., 0, 0 10 r- 1 T-T XT 1 T r u I.- J J Anesth 2004; 18: ft Oal IJ. Naioxone reversal 01 buprenorphine-induced respiratory depression. Clin Pharmacol Ther 1989; 45:

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