Chapter 14
` Buprenorphine: Side Effects and Tolerability
`
` Tabitha Washington and Gilbert J. Fanciullo
`
` Introduction
`
` Buprenorphine is a potent partial opioid agonist and is available in parenteral,
` sublingual, and transdermal applications. Concern regarding its side effect and tol-
`erability profi le, as well as incomplete understanding surrounding its pharmacoki-
`netic and pharmacodynamic profi le has limited its use. Its association with addiction
`treatment has reduced the acceptance of prescribing for its analgesic properties by
`both patients and practitioners. Patients negatively associate the drug with its use in
`addiction and may feel stigmatized when the drug is recommended by their provider
`for treatment of pain [ 1 , 2 ].
` As discussed in previous chapters, buprenorphine is a partial mu opioid agonist
`with a high affi nity for the mu opioid receptor; in addition, it is a nociceptin receptor
`(ORL1) agonist and a kappa receptor antagonist. Its binding at different receptors is
`responsible for its analgesic activity as well as its side effect profi le. An understand-
`ing of these receptors and their actions can help practitioners understand and treat
`side effects from buprenorphine.
` Buprenorphine has partial mu agonistic activity, as compared to the full agonistic
`activity of other opioids such as morphine, oxycodone, and methadone. This means
`that its maximal analgesic effects are less than that of full agonists, and reach a ceil-
`ing where higher doses do not result in increasing effect. Because it is a partial
`agonist, higher doses of buprenorphine can be given with fewer adverse effects such
`as respiratory depression, than are seen with higher doses of full agonist opioids. At
`lower doses, buprenorphine is much more potent than morphine. Individuals who
`are not dependent on opioids have a strong analgesic and positive opioid effect
`when they receive an acute dose of buprenorphine.
`
` T. Washington , MD, MS () • G. J. Fanciullo , MD, MS
` Department of Anesthesiology , Dartmouth Hitchcock Medical Center, Dartmouth Medical
`School , One Medical Center Drive , Lebanon , NH 03756 , USA
` e-mail: Tabitha.A.Washington@kp.org
`
`R.A. Cruciani and H. Knotkova (eds.), Handbook of Methadone Prescribing
`and Buprenorphine Therapy, DOI 10.1007/978-1-4614-6974-2_14,
`© Springer Science+Business Media New York 2013
`
`201
`
`Page 1
`
`RB Ex. 2031
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`202
`
`T. Washington and G.J. Fanciullo
`
` Buprenorphine has a higher affi nity for the mu receptor than other opioids;
` therefore, if a patient is already taking other opioids, buprenorphine introduction
`may displace the existing drug and may precipitate acute opioid withdrawal.
`However, if a patient is already on buprenorphine, it is bound tightly to the mu
`receptor, and therefore does not readily dissociate upon injection of other mu ago-
`nists. Therefore, adding another opioid can help control pain and does not produce
`opioid withdrawal symptoms.
` Buprenorphine’s equivalent analgesic potency as compared to morphine is about
`30 times greater. There is a ceiling for the analgesic effects secondary to the low
`intrinsic activity of buprenorphine at the mu receptor. In the United States, paren-
`teral and transdermal forms are FDA approved for analgesia with usual doses of
`0.3–0.6 mg every 6–8 h. For analgesia, dosing is usually 3–4 times a day as the
`duration of analgesia is 4–8 vs. 24–48 h for opioid withdrawal.
` If a practitioner understands buprenorphines properties, and unique pharmacoki-
`netic and pharmacodynamic aspects, and is comfortable with its use, it will be an
`extremely useful agent for the treatment of patients with chronic pain. This under-
`standing will allow for proper patient selection, outcome measurement, and moni-
`toring in the treatment of pain.
`
` Side Effects
`
` Buprenorphine has a side effect profi le similar to full opioid agonist and can include
`nausea, vomiting, dizziness, constipation, headache, and others [ 3 ], but the intensity
`or severity of side effects may be less than produced by full agonists.
`
` Risk of Abuse, Addiction, Misuse, Overdose, and Tolerance
`
` Abuse has been reported in epidemiological and human clinical studies with patients
`taking buprenorphine [ 4 , 5 ]. Psychological dependence or addiction to buprenor-
`phine can occur in patients following chronic administration. Psychological depen-
`dence is a syndrome characterized by maladaptive behaviors employed to obtain the
`opioid and the continued need for and use of the drug despite its harmful effects.
`Physical dependence is a state in which withdrawal symptoms may occur with
`decreased opioid levels caused by a multitude of scenarios; cessation, dose reduc-
`tion, antagonists, or others. This may also occur with buprenorphine; however, since
`buprenorphine dissociates slowly from the mu opioid receptor, withdrawal symp-
`toms are usually mild [ 6 ]. Withdrawal symptoms are similar in characteristic to
`other opioid discontinuation and can persist for up to 2 weeks. As compared with
`full opioid agonists, patients to whom buprenorphine is administered who are
`already dependent on full mu receptor agonists (such as fentanyl, morphine, oxyco-
`done, etc.) may develop withdrawal symptoms. This is the result of buprenorphines
`
`Page 2
`
`

`

`14 Buprenorphine: Side Effects and Tolerability
`
`203
`
`high affi nity for the mu receptor displacing the full agonist; however, having less
`intrinsic activity at this receptor, it precipitates withdrawal.
` Although there is reported abuse with patients on buprenorphine [ 4 , 5 ], there
`may be a lower incidence of physical dependence and limited development of toler-
`ance secondary to its partial agonist activity. Buprenorphine activates the opioid
`receptor at lower levels, is relatively less reinforcing, and is a less abused opioid. It
`is an option for patients with chronic pain and can be closely monitored by provid-
`ers, as with other opioids. Buprenorphine can be identifi ed in urine toxicology by
`gas chromatography mass spectroscopy (GCMS), however it is costly.
` Although buprenorphine has a better safety profi le than methadone, buprenorphine-
`related overdose deaths have been reported [ 7 – 9 ]. Most of these deaths, similarly to
`full opioid agonists, have occurred with a combination of benzodiazepines or alco-
`hol. In addition, most involved intravenous use of buprenorphine.
` Buprenorphine is a partial agonist; however, its analgesic dose response curve is
`linear over the therapeutic dose range, suggesting it acts as a full agonist in respect
`to analgesia through this range. In patients with chronic opioid use, tolerance can
`develop to the analgesic effects of the opioid requiring higher doses to be adminis-
`tered to produce similar effects. The development of tolerance may be secondary to
`desensitization or down regulation of the mu opioid receptors [ 10 ]. In a study look-
`ing at opioids and their receptors, both fentanyl and morphine were shown to down
`regulate their opioid receptors, while buprenorphine had an increase [ 11 ]. In a study
`of patients maintained on buprenorphine as compared with fentanyl for the treat-
`ment of cancer and noncancer pain, there was a more substantial increase in daily
`dose of fentanyl as compared with buprenorphine [ 12 ].
`
` Respiratory Depression
`
` Buprenorphine is a partial mu opioid agonist and therefore does not activate the mu
`receptor fully, resulting in a ceiling effect that prevents larger doses of the opioid
`from producing greater effects [ 13 ]. This can result in a greater margin of safety
`from death by respiratory depression with increased doses as compared to full ago-
`nist [ 14 , 15 ].
` Buprenorphine has been reported to cause less respiratory depression as com-
`pared with full agonists [ 16 , 17 ]. There are, however, reports of carbon dioxide
`retention in critically ill patients [ 18 ] and is a relative contraindication in severe
`respiratory compromise (hypoxia, hypercapnia, elderly, obstructive disease, central
`nervous system [CNS] depression), as with all opioids. The metabolite of buprenor-
`phine, norbuprenorphine is a potent respiratory suppressant. Dahan et al. [ 19 ]
`showed a nonlinear effect on PaCO 2 , with a ceiling effect at doses greater than
`1.4 µg/kg. In a comparative study of intramuscular buprenorphine 0.3 mg and IM
`morphine 10 mg, there was no difference seen in peak analgesic effect, while
`buprenorphine resulted in little signifi cant change in respiration rate, pulse, or blood
`pressure [ 20 ]. A study showed increasing dose of buprenorphine for analgesia
`
`Page 3
`
`

`

`204
`
`T. Washington and G.J. Fanciullo
`
`increased pain relief with limited respiratory depression, in contrast to fentanyl,
`which caused a dose-related increase in respiratory depression [ 14 ].
` In general, buprenorphine alone is the cause of death in a minority of patients on
`maintenance therapy for addiction. Most deaths were attributed to polysubstance
`abuse with benzodiazepines present. The respiratory depressant effects of buprenor-
`phine may be increased when used in combination with other depressants (alcohol,
`benzodiazepines, and opioids); therefore careful monitoring of patient’s is recom-
`mended. In addition, due to buprenorphine’s tight binding at the opioid receptor,
`buprenorphine-induced respiratory depression may not be fully reversed by the
`administration of a single dose of naloxone and therefore higher and repeated doses
`may be necessary, but can be effective [ 21 ].
`
` Gastrointestinal
`
` The most common side effects of buprenorphine are its gastrointestinal side effects.
`Nausea and vomiting can occur in up to 25 % of patients [ 22 – 24 ]. In a few studies,
`buprenorphine was reported to cause more nausea and vomiting as compared to
`morphine [ 20 , 25 ]. As with other opioids, these symptoms seem to be secondary to
`the direct stimulation of chemoreceptor trigger zones and/or the vestibular system,
`and gastric stasis. If patients develop these symptoms, they may respond to medica-
`tions, including promethazine and serotonin antagonist such as ondasetron. Campora
`et al. surveyed 260 cancer patients for opioid-induced vomiting. The incidence was
`similar to other opioids, 8 % had moderate to severe nausea, and 23 % had nausea
`and vomiting [ 22 ].
` Constipation is a commonly encountered side effect of opioid use that can sig-
`nifi cantly affect a patient’s quality of life. Constipation is due to direct action on
`opioid receptors in the gut wall, decreased intestinal motility, and dehydration of
`stool. The incidence of constipation with buprenorphine has been shown to be lower
`than with morphine use [ 26 – 28 ]. Previous studies have shown that long-term use of
`buprenorphine is associated with a low incidence of constipation [ 29 ]. This may be
`in part due to its preparation; as parenteral or transdermal preparations bypass the
`mu opioid receptors in the intestines. Treatment is similar with all opioids, with a
`focus on prevention by means of stool softeners and a motility agent, and in severe
`cases using a peripheral opiate antagonist (e.g., Alvimopan or methylnaltrexone).
` Hepatitis has been reported in patients taking high doses. Increased liver enzymes
`have been found in patients who are receiving buprenorphine and who have hepati-
`tis C [ 30 ]. In addition, 53 cases of buprenorphine-associated hepatitis were reported
`in France since 1996 [ 27 , 31 , 32 ]. One report suggested an association between
`buprenorphine injection and liver toxicity, possibly from buprenorphines increased
`bioavailability when administered parenterally [ 33 ]. In summary, patients with a
`history of hepatitis C are at increased risk for elevations of liver function tests while
`on buprenorphine; however, these increases appear to be mild and clinically insig-
`nifi cant. Acute intravenous use of buprenorphine can result in high elevations of
`
`Page 4
`
`

`

`14 Buprenorphine: Side Effects and Tolerability
`
`205
`
`liver function tests in patient with a history of hepatitis. Baseline periodic liver
` function tests are recommended in patients receiving buprenorphine and are at
`increased risk of hepatotoxicity (e.g., history of alcoholism, intravenous drug use,
`or preexisting liver disease).
` Patients may also experience abdominal pain, anorexia, diarrhea, or dyspepsia
`with use [ 34 ].
`
` Central Nervous System
`
` As with other opioids, CNS depression can result in impaired cognition, somno-
`lence, and alterations in consciousness. When given in combination with other CNS
`depressants, these attacks can worsen. However, the slightly lower incidence of
`CNS effects with buprenorphine may be a result of its kappa antagonist properties
`[ 29 ]. While buprenorphine can cause headaches, studies have shown a decreased
`incidence of dizziness and headaches in patients on buprenorphine [ 26 , 27 ].
` In general, opioids including buprenorphine can result in increased intracranial
`pressure. Therefore, use these medications cautiously in patients with head injuries,
`intracranial lesions or other circumstances when CSF pressure may be increased.
`
` Cardiac
`
` QT interval prolongation has been associated with buprenorphine use. In clinical
`trials in patients receiving buprenorphine or methadone for treatment of opioid
`dependence, buprenorphine use was associated with less effect on QT interval than
`methadone [ 34 ]. A study of buprenorphine transdermal patch demonstrated QT pro-
`longation at a dose of 40 µg/h. In contrast 10 µg/h did not demonstrate meaningful
`effect on the QT interval [ 34 ].
` Buprenorphine can precipitate hypotension in some patients, similar to other opi-
`oids [ 20 ].
`
` Skin
`
` Allergic reactions from buprenorphine have occurred, although uncommon, ana-
`phylactic shock is possible. Patients using the transdermal system have reported
`skin reactions including pruritus, rash, erythema, and skin irritation around the
`patch site [ 24 , 35 – 37 ]. For patients with pruritus, 1/3 will have resolution of symp-
`toms without patch discontinuation [ 38 ], although patients also usually respond to
`diphenhydramine or hydroxyzine.
`
`Page 5
`
`

`

`206
`
`T. Washington and G.J. Fanciullo
`
` Immune and Endocrine
`
` Most opioids have been found to suppress the immune system to some extent. These
`immunosuppressive effects have been due to their mu receptor agonistic activity
`and are independent of their analgesic effects. Studies in rats have shown that
`buprenorphine shows no immunosuppressive activity [ 39 ]. Although clinical rele-
`vance is yet to be established, buprenorphine may provide a greater margin of safety
`in patients who are immune compromised or at risk for infection.
` Chronic opioid use has been shown to affect the hypothalamo-pituitary axis [ 40 , 41 ].
`Opioid-induced hypogonadism mainly occurs in men [ 42 ] but has been found in
`women as well [ 42 , 43 ]. The symptoms can cause an impact on a patient’s quality
`of life as they may have fatigue, anemia, decreased libido, and depression.
`Buprenorphine has been reported not to affect testosterone levels in the brains of
`male rats [ 44 ]. Moreover, a prospective study looking at women on buprenorphine
`for 6 months, showed no side effects suggestive of hypogonadism [ 45 ]. In a differ-
`ent study of 17 men on maintenance buprenorphine, 37 on methadone, and 51
`healthy blood donors, testosterone levels were higher in the buprenorphine as com-
`pared with the methadone group [ 46 ]. The lack of opioid-induced effects on the
`endocrine system is important to improve tolerability and reduce side effects of
`patients on chronic opioid therapy.
`
` Psychiatric
`
` As with other opioid agonists, buprenorphine is associated with various psychiatric
`effects. In clinical trials the following side effects have been noted; anxiety, fatigue,
`confusion, CNS depression, dizziness, headaches and insomnia, nervousness, and
`vertigo [ 34 ]. Available evidence in patients treated with buprenorphine, indicate no
`clinically signifi cant disruption in cognitive and psychomotor effects [ 13 ].
`
` Special Populations
`
` Practitioners are faced with a wide array of comorbidities in patients with pain.
`There are several populations of patients who although have signifi cant medical
`issues can benefi t from pain control utilizing buprenorphine.
` In patients with hepatic failure, buprenorphine is relatively safe. Lasseter
`et al. found kinetics unaltered by mild or moderate hepatic impairment [ 47 ].
`Buprenorphine, as with other opioids, is predominately metabolized by the liver. If
`metabolism is decreased secondary to liver disease, its analgesic effi cacy may be
`compromised and side effects increased. However, the major metabolic pathway for
`most opioids is oxidation, the exception being morphine and buprenorphine, which
`
`Page 6
`
`

`

`14 Buprenorphine: Side Effects and Tolerability
`
`207
`
`undergo glucuronidation . In patients with hepatic cirrhosis, this pathway is less
`affected by liver disease [ 48 ].
` Patients with renal failure may benefi t from buprenorphine, as the pharmacoki-
`netics of buprenorphine is unaltered in patients with renal failure [ 49 , 50 ].
`Buprenorphine is excreted as an inactive glucuronide of its parent drug, norbu-
`prenorphine, which is unlikely to cause clinically signifi cant side effect [ 51 ]. In
`contrast to buprenorphine, accumulation of morphine’s active metabolite morphine-
`6-glucuronide cautions its use in patients with renal failure. In summary, there is a
`lack of drug accumulation in patients with renal dysfunction [ 52 , 53 ], and doses
`may not need to be altered.
` In elderly patients, buprenorphine may prove to be an easy, safe, and effective
`analgesic.
` Buprenorphine is relatively safe in the elderly as both CYP3A4 and UGT are
`well preserved. In addition, clinical doses of up to 10 mg have shown analgesic
`effi cacy with no respiratory depression [ 14 ]. The low incidence of constipation is
`important in this population as well [ 54 ].
` Buprenorphine is of particular usefulness in patients with preexisting gastroen-
`teritis and intestinal problems as it may improve their quality of life. The transder-
`mal formulation is designed to overcome the pharmacokinetic problems of oral and
`parenteral opioids which include poor GI absorption, fi rst pass metabolism, and low
`bioavailability. The only other transdermal delivery system is fentanyl.
` Opioids have been shown to be effective in some patients with neuropathic pain;
`however, the abnormal pain sensitivity caused by neuropathic pain can oftentimes
`be resistant to opioid therapy, and combination therapy is often established. There
`is a unique analgesic mechanism, as compared with full agonists, such that buprenor-
`phine has shown a pronounced antihyperalgesic effect and may play a role in treat-
`ing severe refractory neuropathic pain [ 55 – 57 ].
`
` Tolerability
`
` In a study comparing buprenorphine vs. morphine for analgesic qualities and side
`effect profi le, buprenorphine was better tolerated with similar analgesic effi cacy
`[ 58 ]. In a subset of patients with chronic pain, the effi cacy of sublingual buprenor-
`phine and sustained-release morphine were similar in analgesia; however, the
`patients treated with buprenorphine had signifi cantly fewer side effects [ 58 ]. A post-
`marketing surveillance study with 13,179 patients showed the side effect of trans-
`dermal buprenorphine to be similar to other opioids. Long-term use was characterized
`by a low rate of constipation (0.97 %), nausea (3.95 %), and dizziness (1.5 %) [ 6 ].
` As discussed previously, buprenorphine can be better tolerated by patients with
`moderate to severe pain. The gastrointestinal adverse events associated with
`buprenorphine have a lower incidence in practice. Constipation, another commonly
`encountered side effect of opioids, incidence with buprenorphine has been shown to
`be lower than with morphine [ 58 , 59 ]. Lastly, CNS-related adverse events that may
`
`Page 7
`
`

`

`208
`
`T. Washington and G.J. Fanciullo
`
`occur in opioid treatment in general has increased incidence in patients with
` declining kidney function. As opposed to other opioids, less than 20 % of buprenor-
`phine is excreted by the kidneys and therefore accumulation is low as comparison
`with morphine or fentanyl where greater than 70 % is excreted by the kidney. Thus,
`buprenorphine has a lower risk of CNS adverse events.
`
` Conclusion
`
` In conclusion, buprenorphine has been a widely used opioid and has been shown to
`be effective for analgesia. Its pharmacokinetics and partial agonistic activity,
`potency, and safety profi le make it a valuable option for patients with chronic pain.
`Buprenorphine is a partial mu agonist with a profi le of effects similar to other mu
`agonists, but has less respiratory depression, constipation, sexual dysfunction, and
`a lower level of physical dependence. In addition, the ability to use a transdermal
`application is invaluable in certain patient populations and a lack of accumulation in
`patients with renal impairment.
`
` References
`
`
`
` 1. Fishman SM, Wilsey B, Yang J, Reisfi eld GM, Bandman TB, Borsook D. Adherence monitor-
`ing and drug surveillance
`in chronic opioid
`therapy. J Pain Symptom Manage.
`2000;20(4):293–307.
` 2. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues.
`J Pain Symptom Manage. 1996;11(4):203–17.
` 3. Radbruch L, Vielvoye-Kerkmeer A. Buprenorphine TDS: the clinical development rationale
`and results. Int J Clin Pract Suppl. 2003;133:15–8; discussion 23–4.
` 4. Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int.
`2001;121(1–2):65–9.
` 5. Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem. 2002;35(7):513–6.
` 6. Tzschentke TM. Behavioral pharmacology of buprenorphine, with a focus on preclinical mod-
`els of reward and addiction. Psychopharmacology (Berl). 2002;161(1):1–16.
` 7. Reynaud M, Petit G, Potard D, Courty P. Six deaths linked to concomitant use of buprenor-
`phine and benzodiazepines. Addiction. 1998;93(9):1385–92.
` 8. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts in France: a
`report on 20 fatalities. J Anal Toxicol. 1998;22(6):430–4.
` 9. Gaulier JM, Marquet P, Lacassie E, Dupuy JL, Lachatre G. Fatal intoxication following self-
`administration of a massive dose of buprenorphine. J Forensic Sci. 2000;45(1):226–8.
` 10. Whistler JL. Examining the role of mu opioid receptor endocytosis in the benefi cial and side-
`effects of prolonged opioid use: from a symposium on new concepts in mu-opioid pharmacol-
`ogy. Drug Alcohol Depend. 2012;121(3):189–204.
` 11. Zaki PA, Keith Jr DE, Brine GA, Carroll FI, Evans CJ. Ligand-induced changes in surface
`mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther.
`2000;292(3):1127–34.
` 12. Sittl R, Nuijten M, Nautrup BP. Changes in the prescribed daily doses of transdermal fentanyl
`and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in
`Germany: results of a retrospective cohort study. Clin Ther. 2005;27(7):1022–31.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 8
`
`

`

`14 Buprenorphine: Side Effects and Tolerability
`
`209
`
` 13. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of
` buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5):569–80.
` 14. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous
`buprenorphine and fentanyl in humans and rats. Br J Anaesth. 2005;94(6):825–34.
` 15. Yassen A, Olofsen E, Dahan A, Danhof M. Pharmacokinetic-pharmacodynamic modeling of
`the antinociceptive effect of buprenorphine and fentanyl in rats: role of receptor equilibration
`kinetics. J Pharmacol Exp Ther. 2005;313(3):1136–49.
` 16. Zenz M, Piepenbrock S, Tryba M, Klauke W, Everlien M. [Sublingual buprenorphine tablets:
`initial clinical experiences
`in
`long-term
`therapy of cancer pain]. Fortschr Med.
`1983;101(5):191–4.
` 17. Radbruch L, Sabatowski R, Petzke F, Brunsch-Radbruch A, Grond S, Lehmann KA.
`Transdermal fentanyl for the management of cancer pain: a survey of 1005 patients. Palliat
`Med. 2001;15(4):309–21.
` 18. Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a
`new antinociceptive agent. Br J Pharmacol. 1977;60(4):537–45.
` 19. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depres-
`sion but not in analgesia. Br J Anaesth. 2006;96(5):627–32.
` 20. Kjaer M, Henriksen H, Knudsen J. A comparative study of intramuscular buprenorphine and
`morphine in the treatment of chronic pain of malignant origin. Br J Clin Pharmacol.
`1982;13(4):487–92.
` 21. Pergolizzi J, Aloisi AM, Dahan A, et al. Current knowledge of buprenorphine and its unique
`pharmacological profi le. Pain Pract. 2010;10(5):428–50.
` 22. Campora E, Merlini L, Pace M, et al. The incidence of narcotic-induced emesis. J Pain
`Symptom Manage. 1991;6(7):428–30.
` 23. Noda J, Umeda S, Arai T, Harima A, Mori K. Continuous subcutaneous infusion of buprenor-
`phine for cancer pain control. Clin J Pain. 1989;5(2):147–52.
` 24. Likar R, Kayser H, Sittl R. Long-term management of chronic pain with transdermal buprenor-
`phine: a multicenter, open-label, follow-up study in patients from three short-term clinical
`trials. Clin Ther. 2006;28(6):943–52.
` 25. Tantucci C, Paoletti F, Bruni B, et al. Acute respiratory effects of sublingual buprenorphine:
`comparison with
`intramuscular morphine.
`Int J Clin Pharmacol Ther Toxicol.
`1992;30(6):202–7.
` 26. Fudala PJ, Bridge TP. Foreword to: buprenorphine and buprenorphine/naloxone: a guide for
`clinicians. Drug Alcohol Depend. 2003;70(2 Suppl):S1–2.
` 27. Ling W, Charuvastra C, Collins JF, et al. Buprenorphine maintenance treatment of opiate
`dependence: a multicenter, randomized clinical trial. Addiction. 1998;93(4):475–86.
` 28. Robbie DS. A trial of sublingual buprenorphine in cancer pain. Br J Clin Pharmacol. 1979;7
`(Suppl 3):315S–7.
` 29. Przeklasa-Muszynska A, Dobrogowski J. Transdermal buprenorphine in the treatment of can-
`cer and non-cancer pain—the results of multicenter studies in Poland. Pharmacol Rep.
`2011;63(4):935–48.
` 30. Petry NM, Bickel WK, Piasecki D, Marsch LA, Badger GJ. Elevated liver enzyme levels in
`opioid-dependent patients with hepatitis treated with buprenorphine. Am J Addict. Summer
`2000;9(3):265–9.
` 31. Fudala PJ, Bridge TP, Herbert S, et al. Offi ce-based treatment of opiate addiction with a
`sublingual- tablet
`formulation of buprenorphine and naloxone. N Engl J Med.
`2003;349(10):949–58.
` 32. Auriacombe M, Fatseas M, Franques-Reneric P, Daulouede JP, Tignol J. [Substitution therapy
`in drug addictions]. Rev Prat. 2003;53(12):1327–34.
` 33. Berson A, Gervais A, Cazals D, et al. Hepatitis after intravenous buprenorphine misuse in
`heroin addicts. J Hepatol. 2001;34(2):346–50.
` 34. Purdue Pharmaceuticals. Butrans® (buprenorphine) transdermal system package insert.
`Richmond, VA; 2010.
`
`Page 9
`
`

`

`210
`
`T. Washington and G.J. Fanciullo
`
` 35. Sittl R, Griessinger N, Likar R. Analgesic effi cacy and tolerability of transdermal buprenorphine
`in patients with inadequately controlled chronic pain related to cancer and other disorders: a
`multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. 2003;25(1):
`150–68.
` 36. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase
`III, multicenter,
`randomized, double-blind, placebo-controlled
`study. Clin Ther.
`2004;26(11):1808–20.
` 37. Radbruch L. Buprenorphine TDS: use in daily practice, benefi ts for patients. Int J Clin Pract
`Suppl. 2003;133:19–22; discussion 23–4.
` 38. Likar R, Griessinger N, Sadjak A, Sittl R. [Transdermal buprenorphine for treatment of chronic
`tumor and non-tumor pain]. Wien Med Wochenschr. 2003;153(13–14):317–22.
` 39. Sacerdote P. Opioids and the immune system. Palliat Med. 2006;20(Suppl 1):s9–15.
` 40. Meczekalski B, Podfi gurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional
`hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol.
`2008;24(1):4–11.
` 41. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain.
`2002;3(5):377–84.
` 42. Aloisi AM, Pari G, Ceccarelli I, et al. Gender-related effects of chronic non-malignant pain
`and opioid therapy on plasma levels of macrophage migration inhibitory factor (MIF). Pain.
`2005;115(1–2):142–51.
` 43. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids
`for control of nonmalignant pain. J Pain. 2008;9(1):28–36.
` 44. Ceccarelli I, De Padova AM, Fiorenzani P, Massafra C, Aloisi AM. Single opioid administra-
`tion modifi es gonadal steroids in both the CNS and plasma of male rats. Neuroscience.
`2006;140(3):929–37.
` 45. Aurilio C, Ceccarelli I, Pota V, et al. Endocrine and behavioural effects of transdermal
`buprenorphine
`in pain-suffering women of different reproductive ages. Endocr J.
`2011;58(12):1071–8.
` 46. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmuller D. Plasma
`testosterone and sexual function in men receiving buprenorphine maintenance for opioid
`dependence. J Clin Endocrinol Metab. 2005;90(1):203–6.
` 47. Lasseter KC, Venitz J, Eltahtawy A, et al. Systemic pharmacokinetic (PK) study of buprenor-
`phine (B) in mild to moderate chronic hepatic impairment (CHI). Clin Pharmacol Ther.
`2001;69:P2.
` 48. Tegeder I, Geisslinger G, Lotsch J. [Therapy with opioids in liver or renal failure]. Schmerz.
`1999;13(3):183–95.
` 49. Deng J, St Clair M, Everett C, Reitman M, Star RA. Buprenorphine given after surgery does
`not alter renal ischemia/reperfusion injury. Comp Med. 2000;50(6):628–32.
` 50. Summerfi eld RJ, Allen MC, Moore RA, Sear JW, McQuay HJ. Buprenorphine in end stage
`renal failure. Anaesthesia. 1985;40(9):914.
` 51. Bennett WM, Aronoff GR, Morrison G, et al. Drug prescribing in renal failure: dosing guide-
`lines for adults. Am J Kidney Dis. 1983;3(3):155–93.
` 52. Filitz J, Griessinger N, Sittl R, Likar R, Schuttler J, Koppert W. Effects of intermittent hemo-
`dialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain
`patients treated with transdermal buprenorphine. Eur J Pain. 2006;10(8):743–8.
` 53. Mercadante S, Arcuri E. Opioids and renal function. J Pain. 2004;5(1):2–19.
` 54. Griessinger N, Sittl R, Likar R. Transdermal buprenorphine in clinical practice—a post-
`marketing surveillance study in 13,179 patients. Curr Med Res Opin. 2005;21(8):1147–56.
` 55. Likar R, Sittl R. Transdermal buprenorphine for treating nociceptive and neuropathic pain:
`four case studies. Anesth Analg. 2005;100(3):781–5, table of contents.
` 56. Hans G. Buprenorphine—a review of its role in neuropathic pain. J Opioid Manag.
`2007;3(4):195–206.
`
`Page 10
`
`

`

`14 Buprenorphine: Side Effects and Tolerability
`
`211
`
` 57. Induru RR, Davis MP. Buprenorphine for neuropathic pain--targeting hyperalgesia. Am J
`Hosp Palliat Care. 2009–2010;26(6):470–3.
` 58. Wolff RF, Aune D, Truyers C, et al. Systematic review of effi cacy and safety of buprenorphine
`versus fentanyl or morphine in patients with chronic moderate to severe pain. Curr Med Res
`Opin. 2012;28(5):833–45.
` 59. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating
`moderate- severe cancer pain in comparison to long-acting morphine: a meta-analysis and
` systematic review of the literature. J Palliat Med. 2008;11(3):492–501.
`
`Page 11
`
`