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Cia_1880_vadivelu.inddManagement of chronic pain in the elderly: focus on transdermal buprenorphine Abstract: Chronic pain in the elderly is a signiﬁ cant problem. Pharmacokinetic and metabolic
changes associated with increased age makes the elderly vulnerable to side effects and overdosing associated with analgesic agents. Therefore the management of chronic cancer pain and chronic nonmalignant pain in this growing population is an ongoing challenge. New routes of administration have opened up new treatment options to meet this challenge. The transdermal buprenorphine matrix allows for slow release of buprenorphine and damage does not produce dose dumping. In addition the long-acting analgesic property and relative safety proﬁ le makes it a suitable choice for the treatment of chronic pain in the elderly. Its safe use in the presence of renal failure makes it an attractive choice for older individuals. Recent scientiﬁ c studies have shown no evidence of a ceiling dose of analgesia in man but only a ceiling effect for respiratory depression, increasing its safety proﬁ le. It appears that transdermal buprenorphine can be used in clinical practice safely and efﬁ caciously for treating chronic pain in the elderly.
Keywords: transdermal buprenorphine, chronic pain, elderly
Many chronic pain patients are elderly (ie, Ͼ65 years of age) (Sittl 2006) and a
signiﬁ cant number of these experience chronic pain which can affect their normal
functioning and quality of life (Gagliese and Melzack 1997). Difﬁ culty in assessing the quality and intensity of pain due to cognitive changes and the presence of multiple medical problems associated with aging contributes to undertreatment of pain in this population. However, pharmacokinetic and metabolic changes associated with increased age make these patients more vulnerable to the potential side effects and overdosing with analgesic agents. Therefore, management of chronic pain due to cancer or persistent neuropathic pain (McQuay 2002; Foley 2003) is a challenge, especially in the growing population of elderly patients.
Chronic pain treatment in the elderly is multidimensional and includes noninvasive as well as invasive therapies. Invasive therapies include pharmacological therapies with nonopioid, opioid, and adjuvant medications. New routes of administration of drugs have opened up new treatment options for the treatment of chronic pain in the elderly (Grond et al 2000). In this context buprenorphine, a semi-synthetic, lipophilic, unique opioid analgesic, has broad clinical applications (Vadivelu and Hines 2007). Buprenorphine is being used sublingually (Book et al 2007) and intrathecally (Shah et al 2003) for the treatment of acute pain and transdermally for the treatment of chronic pain (Graziotti and Goucke 1997; Simpson 2002; Budd 2003; Likar et al Department of Anesthesiology, Yale University, 333 Cedar Street, New Haven, 2003). Its long-acting analgesic property and relative safety administered in this form make it useful for the treatment of chronic pain in the elderly. This review focuses on the use of transdermal buprenorphine for the treatment of chronic pain Clinical Interventions in Aging 2008:3(3) 421–430 2008 Dove Medical Press Limited. All rights reserved Chronic pain management
interventions. It is recommended that the least invasive and in the elderly
simple interventions be tried ﬁ rst in the elderly before use Chronic pain increases with age (Crook et al 1984) due to Chronic pain control in the elderly by all these therapeutic increases in the incidence of diseases such as arthritis, can- measures is still inadequate. The recent development of cer, diabetes mellitus, and cardiovascular and neurological transdermal buprenorphine has opened up new treatment diseases (Priano et al 2006). Detection and management of options for treatment of chronic pain in this growing patient chronic pain in the elderly is often inadequate and continues group. It has unique pharmacodynamics which could make to pose a challenge for practitioners (Woo et al 1994). The it a useful analgesic in the presence of age-related cognitive, detection of chronic pain in the elderly can be done with metabolic, and pharmacokinetic changes so often seen in the a pain scoring pain system which assesses the severity of elderly. The pharmacokinetics of buprenorphine, especially its the patient’s pain subjectively on a score of from 1 to 10. slow association and disassociation rate at the receptor sites, The detection of pain in the elderly may be complicated make it useful for use in the elderly (Yassen et al 2005).
by the presence depression and dementia. Dementia and confusion make the assessment of pain sometimes unreliable Pharmacodynamics
with resultant difﬁ culty in applying the conservative and interventional therapies in these patients.
Elderly patients with depression report more pain than Originally, buprenorphine was thought to be 25–50 times those who are not depressed (Casten et al 1995), and com- more potent by weight than morphine in an equivalent dose plaints of pain may be the ﬁ rst sign of dementia (Kisely et al (Jasinski et al 1978), but it is now thought that buprenor- 1992). Chronic pain in the elderly can be either nociceptive phine is 75–100 times more potent than morphine (Sittl or neuropathic. The conservative therapies for these states et al 2006). Buprenorphine is a centrally acting partial mu include adequate nutrition, cognitive and behavioral thera- agonist and a kappa and delta opioid receptor antagonist pies, rehabilitational pain medicine, biofeedback, relaxation, (Negus et al 2002). Buprenorphine has a high afﬁ nity for and alternative medicine techniques such as acupuncture and the mu receptor and a lower intrinsic activity than a full acupressure. Low level activity programs also can beneﬁ t the agonist mu opioid receptor agonist (Cleeland et al 1994). elderly physically (Helme et al 1989).
It appears that the mu agonist effect is most important for Nonsteroidal anti-inﬂ ammatory drugs are commonly producing its analgesic results. Buprenorphine can produce used to treat nociceptive pain and inhibit prostaglandin pro- near maximal mu receptor occupation, thereby decreasing duction. Malignant pain is often treated in the elderly with mu opioid receptor availability, and replace agonist effects opioids which can be used also for treatment of neuropathic and alleviate withdrawal symptoms (Greenwald et al 2003). nonmalignant pain. Due to high fat to protein ratios, opioids Buprenorphine produces stabilization of mu receptors in the in the elderly should be started at doses 25%–50% lower submembrane level and increases the expression of mu recep- than those used in young adults, with rescue doses limited to tors on membranes (Evans and Easthope 2003). By affecting 5% of the total daily dose available every 4 hours (Abrahm the mu receptor, reserve buprenrophine can enable the switch 2000). Commonly used opioids in the elderly are oxycodone, from another opioid to buprenorphine. The mu agonist effect morphine, hydromorphone, and fentanyl patch. Oxycodone of buprenorphine is in the form of a bell-shaped curve. In is a preferred drug in the elderly since it has a short half-life animal models, the bell-shaped analgesic dose response and no toxic metabolites, and is available in both the short- curve peaks at 1 mg/kg, which is below the highest dose of and long-acting forms. Morphine can be used with caution, paying attention to renal insufﬁ ciency and sedation.
Buprenorphine interacts with orphanin FQ/nociceptin Common adjuvant medications for the treatment of receptor ORL-1 in the spinal cord and the brain stem. nonmalignant neuropathic pain in the elderly include a Buprenorphine activates ORL1 in the spinal cord, which variety of medications such as nonopioid analgesics, opioid appears to be analgesic. OR-1 activation in the brain stem analgesics, adjuvant medications including antidepressants, blocks opioid analgesic responses and contributes to the partial anticonvulsants, tramadol, and capsaicin. The invasive agonist property of buprenorphine (Bloms-Funke et al 2000). techniques include neuromodulatory or surgical interven- Buprenorphine also possesses an antihyperalgesic effect tions such as nerve blocking, spinal cord stimulation and relative to clinically used mu agonists; its antihyperalgesic intraspinal, implantable drug delivery, and neurodestructive effects exceed its analgesic effects (Simonnet and Rivat 2003; Clinical Interventions in Aging 2008:3(3) Transdermal buprenorphine for chronic pain in the elderly Koppert et al 2005; Simonnet 2005). It is thought that the opioid receptors from the cell surface, as did morphine antihyperalgesic effect of buprenorphine may be related to and fentanyl. Buprenorphine was unable to trigger mu receptor internalization because it has a low efﬁ cacy for Buprenorphine is associated with a long duration of activating G proteins. Sittl et al (2005), who studied the use action, 6–8 hours (Johnson et al 2005), which has been of transdermal fentanyl and transdermal buprenorphine in attributed to the slow dissociation of buprenorphine from humans, found a signiﬁ cant increase in the mean daily dose the mu receptor (Jasinski et al 1978). The transdermal of fentanyl over buprenorphine in this time period. The long buprenorphine formulation has a slow onset (12–24 hours) analgesic action of buprenorphine as well as its decreased and a long duration of action (3 days) (Sorge and Sittl 2004). tolerance because of loss of opioid receptors from the cell Increased sensitivity to the depressant actions of opioids in surface make it suitable the treatment of chronic pain in the elderly is well established. Fentanyl as a transdermal preparation is not recommended for used in opioid-naïve patients because of the incidence of respiratory depression Metabolism and elimination
The metabolism of buprenorphine is mediated by cytochrome Clinically relevant doses of up to 10 mg of buprenor- P450 in the liver (Heel et al 1979). Buprenorphine is oxidized phine have shown full dose-dependent effects on analgesia to N dealkyl buprenorphine, also called norbuprenorphine by with no respiratory depression (Dahan et al 2005). Dahan CYP3A4. Most opioids with the exception of buprenorphine et al (2006) have shown a ceiling to respiratory depression and morphine undergo oxidation, and buprenorphine and but not to analgesia over a dose range from 0.05 to 0.6 mg morphine undergo glucuronidation. Both buprenorphine and buprenorphine in humans This safety proﬁ le could give norbuprinorphine undergo rapid glucuronidation. The bind- transdermal buprenorphine a preferred role over transdermal ing to glucuronic acid leads to a low bioavailability of 5% fentanyl for treatment of chronic pain in the elderly. In with oral buprenorphine. Norbuprenorphine is 10 times more humans, there is also a less marked effect of buprenorphine potent than buprenorphine in causing respiratory depression. binding to mu opioid receptors on gastrointestinal transit However, this respiratory depressant effect of norbuprenor- times, and indeed constipation seen in the clinic is remarkably phine can be antagonized by naloxone (Gal 1989) and also by the substance beta-ﬂ unaltrexamine. It also has a weak There was initial concern that the partial agonism of mu agonist effect that is seen after chronic use. Most of the buprenorphine would lead to limited analgesia and would concentration of norbuprenorphine has been seen in the lungs prevent other opioids from effectively binding. It has since rather than in the brain (Ohtani et al 1997).
been shown that buprenorphine is a strong analgesic, with Buprenorphine is metabolized to glucuronide metabolites no ceiling effect for analgesia (Jasinski et al 1978; Budd and which can be hydrolyzed in the intestine to release buprenor- Collett 2003). It does not produce persistent binding of the mu phine again. The released buprenorphine can be reabsorbed receptor, which would prevent the action of other opioids in via the enterohepatic circulation. Excretion of buprenorphine acute and chronic painful conditions (Walsh et al 1995); as a and metabolites is 70% by feces of unchanged buprenor- result other opioids can be used for breakthrough pain in the phine, conjugated buprenorphine, and the Phase I conjugated presence of buprenorphine (Budd and Collett 2003).
metabolites. The other small quantity of buprenorphine- related substances is excreted in the urine (Budd 2003). Decreased tolerance
Unconjugated buprenorphine does not appear in urine, only In humans exposed to opioids, but not physically depen- in stool secondary to fecal ﬂ ora beta-glucuronidase (Cone dent on them, a study of volunteers receiving sublingual buprenorphine in ascending doses of 1 to 32 mg demon- Age-related changes in drug kinetics
strated no ceiling effect for its analgesia effects (Walsh et al 1994). In physically dependent individuals, acute cessation and dynamics relevant to opioids
of buprenorphine may lead to withdrawal symptoms that The narrowing of the therapeutic index because of appear to be milder than those seen with morphine (Heel physiological changes in aging can alter the pharmacokinetics et al 1979). Zaki et al (2000) studied equal concentrations and pharmacodynamics of analgesics. Important changes are (10 μM/L) of morphine, fentanyl, and buprenorphine, seen with age which can affect opioid drug kinetics and and showed that buprenorphine did not induce the loss of dynamics. Hepatic blood flow decreases with age and Clinical Interventions in Aging 2008:3(3) age-related changes occur in cytochromes and conjugases Buprenorphine pharmacokinetics are stable in mild to are. These changes can narrow the therapeutic index and moderate hepatic impairment (Johnson et al 2005).
increase the risk of toxicity and drug-drug interactions (Davis and Srivastava 2003). Distribution of drugs to the Side effects
central nervous system (CNS) are altered with alterations in Buprenorphine can cause nausea, vomiting, sedation, receptors and transmitters. These CNS changes can increase euphoria, papillary constriction, delayed gastric emptying, risk of delirium. In addition changes in renal function can and respiratory depression. Buprenorphine in high doses can increase liver enzymes due to accumulation within Buprenorphine in the presence
Sedation should be observed with the use of buprenorphine renal impairment
because sedatives are known to cause pharmacodynamic Renal impairment leading to a decrease in renal excretory interactions (Clarot et al 2003). In humans, dose-response studies function is common in elderly patients due to advanced age on respiratory depressive response showed data characterized (Balázs et al 2008) or to co-morbid conditions such as dia- by a bell-shaped curve in which respiratory depression response betes or hypertension. Buprenorphine for treatment of pain increases with increasing dose of buprenorphine in the lower can be administered in normal doses in the elderly, because dose ranges (Walsh et al 1995). This bell-shaped effect for it is excreted mainly in the liver (Brewster et al 1981; Cone respiratory depression suggests a decreased likelihood of et al 1984). In contrast, most opioids have to be cleared by respiratory depression with buprenorphine at higher doses, the kidney and so have to be used in smaller doses, or with suggesting increased safety of the drug. The same bell-shaped decreased frequency or not used at all in the elderly. Though curve has not been shown for the other buprenorphine-related the levels of norbuprenorphine may be increased by continu- mu opioid agonist effects of analgesia, euphoria, sedation, and ous intravenous infusions of buprenorphine in renal failure papillary constriction (Jasinski et al 1978). Nausea, vomiting, (Summerﬁ eld et al 1985), it most likely does not produce and constipation can occur with buprenorphine as with other untoward effects because of the lower potency and lower opioids; however, it has been shown that these side effects afﬁ nity of norbuprenorphine compared with buprenorphine occur signiﬁ cantly less with buprenorphine than with morphine (Hand et al 1990). Buprenorphine can be used in elderly patients with impaired renal function and chronic renal Comparison of side effects
insufﬁ ciency, and in hemodialysis patients in whom its phar- macokinetics are unchanged. Filitz et al (2006) studied the with other opioids
disposition of buprenorphine and its metabolite norbuprenor- Buprenorphine appears to have a greater margin of safety phine in 10 patients with end-stage kidney disease treated than other potent opioids such as fentanyl when used to treat with transdermal buprenorphine. The blood samples studied chronic pain. Dahan et al (2005) compared the respiratory showed no increase in levels of buprenorphine and norbu- effects of buprenorphine and fentanyl given intravenously prenorphine at up to 70 μg/hour transdermal buprenorphine. in healthy human volunteers. Buprenorphine-induced respi- Stable analgesic effects as seen by unchanged buprenorphine ratory depression had a maximum (ceiling) effect at doses plasma levels in the presence of hemodialysis were also seen of Ͼ0.1 mg/70 kg (Dahan et al 2005). In another study by in the presence of a transdermal buprenorphine patch. Its Dahan et al (2006), a ceiling effect in respiratory depres- safety for use in the presence of renal impairment is a major sion, but not in analgesia, was demonstrated in a study on advantage over other opioids in the elderly.
20 volunteers over a weight-adjusted dose range of 0.2–0.4 mg/70 kg. The peak analgesic effect of buprenorphine was Buprenorphine in hepatic disease
increased by doubling the dose, and the timing and magnitude Buprenorphine at high doses increases liver enzymes due to of respiratory depression as seen by sedation and respira- accumulation within mitochondria. Liver function is impor- tory rate remained unchanged. Of note, its analgesic effect tant because buprenorphine is metabolized by CYP3A4, had no plateau. Buprenorphine may thus have full agonist resulting in norbuprenorphine. Both are rapidly glucuroni- effect for analgesia and a partial agonist effect for respira- dated by UCT1A1 and UGT2B7, and these processes occur tory depression at mu receptors, showing a differential effect in the liver. Unconjugated buprenorphine is excreted in the on analgesia and respiration. It appears that its respiratory bile (Kintz 2002; Clarot et al 2003).
effects are limited, unlike morphine and fentanyl which Clinical Interventions in Aging 2008:3(3) Transdermal buprenorphine for chronic pain in the elderly have been shown to have no ceiling effect for analgesia but patient compliance, an extremely important factor in elderly which can cause severe respiratory depression and apnea in high doses. No detrimental effect from chronic exposure to The purpose of the transdermal patch is to provide long- buprenorphine has been shown on corticosensitive immune term pain relief and to avoid an increase in adverse side parameters (D’Elia et al 2003). Gomez-Flores and Weber effects. The transdermal buprenorphine patch is available in (2000) showed that buprenorphine, unlike morphine, was 3 strengths, containing 20, 30, or 40 mg of buprenorphine, not associated with immunosuppression and did not activate which can deliver 35, 52.5, or 70 μg/hour over 72 hours, the hypothalamic–pituatary axis. The lack of effects on the respectively. It is generally recommended that patients immune system is thought to be related to its partial agonist who have not taken any analgesic or a nonopioid analgesic should start with a 35 μg/hour patch. This long-acting form of buprenorphine can be supplemented with the short-acting Routes of administration
form of sublingual buprenorphine for breakthrough pain. If Several new routes for delivery of the buprenorphine are now the patch is used, the time to minimum therapeutic concentra- available and have been used to provide analgesia, including tion is 21 hours. After the placement of a transdermal patch the buprenorphine/naloxone combination and transdermal additional analgesics should be available as needed for 24–48 buprenorphine. The parenteral forms of buprenorphine, such hours for treatment of breakthrough pain, because plasma as subcutaneous, intramuscular, epidural, and intrathecal, levels of buprenorphine rise slowly after patch application. have been available since 1981. Sublingual buprenorphine All opioid-naïve patients, especially the elderly, should be has a much longer half-life than parenteral buprenorphine started with the lowest strength patch.
because of sequestration in buccal and sublingual fat. Transdermal buprenorphine
Because transdermal buprenorphine is not commercially available in the US, most clinicians who use the drug often for treatment of chronic pain
convert from intravenous/subcutaneous infusions to sublin- Transdermal buprenorphine has been shown to be useful for the treatment of chronic pain associated with cancer as well Buprenorphine is a lipophilic, synthetic opioid; these as noncancer etiologies (Sittl et al 2003). Likar et al (2003) properties, combined with its low molecular weight, make studied the analgesic efﬁ cacy and tolerability of transder- it suitable for transdermal delivery. Average half-life is 37 mal buprenorphine in patients with inadequately controlled hours. Its properties of high afﬁ nity and slow dissociation chronic pain. They demonstrated that buprenorphine is an combined in a slow-release transdermal form can produce effective analgesic for chronic pain. It was shown that trans- long-term pain relief with fewer side effects, making it suit- dermal buprenorphine patches are useful for the treatment of able for treating persistent chronic pain of long duration in moderate to severe cancer pain and also for noncancer pain the elderly in whom wide swings of drug concentration are that is severe and unresponsive to nonopioid analgesics. less well tolerated. Transdermal buprenorphine has a half-life About one third of study patients with chronic pain had of about 30 hours. Sublingual buprenorphine can be given satisfactory analgesia with the administration of buprenor- for breakthrough pain. In a long-term study, sublingual phine. In addition transdermal buprenorphine was found to buprenorphine was available for use as needed for control decrease the need for rescue medications and increases the duration of pain-free sleep. Likar et al (2006) also studied The transdermal route is especially useful for drugs the efﬁ cacy and tolerability of long-term treatment with such as buprenorphine which have limited bioavailability if transdermal buprenorphine patients with chronic persistent given orally. Transdermal buprenorphine can provide pain pain of moderate to severe intensity who had previously relief for cancer and for chronic noncancer pain (Likar et al received buprenorphine in 3 short-term clinical trials. They 2003; Pavelka et al 2004; Muriel et al 2005). Transdermal studied 134 patients with cancer-related pain and 105 patients buprenorphine formulated in an adhesive polymer matrix with pain of noncancerous origin. The mean duration of (acrylate vinyl acetate) is being widely used clinically for participation was 7.5 months and the adherence to therapy the treatment of moderate to severe cancer pain (Budd and was 78.7%. This level of adherence to therapy would be of Collett 2003; Sittl et al 2006). The transdermal buprenorphine patch available in matrix form does not allow for dose dump- Neuropathic pain or chronic persistent pain often presents ing in the event of damage to the patch and also improves as burning, lancinating pain caused by injury or chronic Clinical Interventions in Aging 2008:3(3) changes to peripheral or central nerves (McQuay 2002) and No development of tolerance was seen clinically in these has been found to be difﬁ cult to treat with conventional patients and the patches were well tolerated. In a randomized analgesics (Foley 2003). There is increasing evidence controlled study by Pace et al (2007), patients with chronic that opioids can decrease neuropathic pain in peripheral cancer had better pain control, and improved mental health and central areas though the response can be variable and vitality with the use of transdermal buprenorphine (Rowbotham et al 2003). For example morphine, a typical compared with sustained-release morphine. Transdermal mu opioid agonist, is not very sensitive in treating neuro- buprenorphine appears to be well tolerated and effective pathic pain (Mao et al 1995). It has been suggested that the for the treatment of chronic cancer and chronic noncancer ineffectiveness of morphine in controlling neuropathic pain may be due to the downregulation of opioid receptors after nerve injury in the sensory neurons and in the spinal cord Advantages in the elderly
(Zhang et al 1998). In contrast, buprenorphine, a stronger Elderly patients need special consideration with several fac- opioid, has been shown in rats and humans to be effective in tors related to drug delivery, including drug delivery itself, controlling neuropathic pain. It is known that some opioids drug interactions, and adherence to prescribed regimens. have an NMDA blocking effect. Ebert et al (1995, pp. 165–8) Transdermal drug delivery systems have advantages over have shown that buprenorphine is one such opioid that can other routes of drug administration especially in the elderly block NMDA receptors and reduce reﬂ ex facilitation and (Pepe et al 1988). The transdermal route is suited for the central sensitization (Kouya et al 2002).
elderly as it provides ease of use for the patient and the care- Mechanical and cold allodynia and hyperalgesia were taker, provides greater adherence to prescribed regimens, and alleviated in rats with neuropathic pain behaviors (Kouya has less risk of toxicity and dose dumping. This is especially et al 2002). Human studies have also shown similar results. important because of the increased need for medications in Intravenous buprenorphine has been shown to relieve long- older age when there is a higher incidence of chronic condi- term neuropathic pain in patients after thoracotomy (Benedetti tions such as chronic pain, diabetes mellitus, cardiovascular et al 1998). In another study, phantom limb pain was relieved disease, and neurological diseases such as Parkinson’s dis- by intrathecal buprenorphine after amputation (Omote et al ease and Alzheimer’s disease. A transdermal delivery system 1995). Buprenorphine given by the transdermal route has also is also useful when elderly patients are unable to tolerate providef adequate pain relief in cases of neuropathic pain, oral medications or are unwilling to swallow oral medica- as shown in 3 patients with chronic nonmalignant pain due tions. Transdermal medications also avoid needle punctures to musculoskeletal diseases (Balint 2002).
associated with subcutaneous or intravenous routes and are Transdermal buprenorphine has been used for “opioid less labor intensive than these routes (Jiang et al 1997). It rotation”, which is a method to treat chronic pain refractory has been stated that transdermal delivery results in reason- to treatment by other opioids for long-term pain relief. In a ably constant plasma drug concentrations because of its rate opioid rotation study (Freye et al 2007), 42 patients (mean age 64.1 years) receiving high-dose morphine (120–240 Transdermal buprenorphine has several advantages over mg/day) for chronic pain secondary to neuropathic, mus- the conventional methods of administration in the elderly: culoskeletal, or malignant etiology were switched to trans- it results in no peak trough effects and a slower increase in dermal buprenorphine because of intolerable side effects serum concentration, resulting in fewer adverse events in and insufﬁ cient pain relief. The patients were followed for serum concentrations compared with sublingual buprenor- more than 10 weeks. Patients reporting very good pain relief phine (Bohme 2002; Johnson et al 2005). The use of drugs increased from 5% to 75% and those reporting improved with an absence of peak trough effects is in accordance with quality of sleep increased from 14% to 74%. There was no WHO guidelines, which recommend that to decrease adverse tolerance to buprenorphine via this route and only 11.9% side effects, drugs should be used to treat chronic pain that of adverse effects were noted, mostly due to local irrita- do not induce sudden peaks in serum concentrations. The tion. Chronic pain of cancer and noncancer origin was also absorption of transdermal buprenorphine among patients reported to be effectively treated in all ages Ͼ70 years in varies less than among patients on transdermal fentanyl another study by Griessinger et al (2005), in which a total (Jensen et al 2007). Transdermal fentanyl absorption has of 13,179 chronic pain patients were evaluated. In this been thought to decrease in the elderly, resulting in many study 28% had cancer pain and 72% had noncancer pain. dose adjustments. Since the absorption of transdermal Clinical Interventions in Aging 2008:3(3) Transdermal buprenorphine for chronic pain in the elderly buprenorphine is little affected with age, its relative potency will increase in the elderly. It has been suggested that fewer The high afﬁ nity to the mu receptor enables buprenorphine dosage adjustments are needed in patients using transdermal to exert its analgesic effect for a long duration, eliminating buprenorphine compared with patients using transdermal the need for daily dosing and overcoming problems of non- fentanyl. This was shown in a retrospective analysis on data adherence to treatment regimens which is common in the from 400 medical practices in Germany which showed a elderly. This property will also decrease the risk of death signiﬁ cantly greater increase in mean daily dosage in patients treated with transdermal fentanyl compared with patients treated with transdermal buprenorphine (Sittl et al 2006). Drug interactions in the elderly
The painful conditions included cancer, osteoarthritis, low To establish specific safety guidelines, the use of buprenorphine in the elderly with other drugs requires The reduced need to escalate transdermal buprenor- further investigation, especially as many elderly patients phine relative to transdermal fentanyl is probably related are using many different pharmacological agents such to the antihyperalgesic effect, which prevents or blocks as treatment for heart disease and cognitive dysfunction. hyperadaptive responses differing from fentanyl (Célèrier Common medications of the elderly include beta blockers, et al 2000; Angst et al 2003; Koppert et al 2005). Incidence statins, and ACE-inhibitors. Buprenorphine has been known of chronic pain conditions increases with advancing age. to inhibit the cytochrome P 450 system by inhibiting the Increased back pain due to osteoporotic and compression CYP3A4- and CYP2D6-mediated reactions. It is thought, fractures are common in the elderly (Gandy and Payne however, that the clinical concentrations used are unlikely to 1986) and transdermal buprenorphine, by virtue of its dos- affect signiﬁ cantly metabolism of drugs that are metabolized age stability, could be used to treat these conditions safely by cytochrome P 450 (Umehara et al 2002). It is known than CYP3A4 and UCTiA3 are relatively preserved in the The low incidence of adverse events associated with elderly. Drugs that interact with CYP3A4 will not prevent buprenorphine lends an added attraction for use in the conjugation, which is rate limiting. Buprenorphine interacts elderly who have decreased tolerance to adverse effects. with CYP3A4 differently than methadone. It is seem In the elderly the transdermal patch is ideal because it can that ﬂ uvoxamine, which blocks CYP3A4 and methadone be easily applied, resulting in greater compliance in this metabolism, does not interfere with buprenorphine clearance population who tend to be more forgetful. It also has a lower susceptibility to the development of toxicity and opioid abuse Buprenorphine cannot be dialyzed and very high doses because it adheres strongly and is less susceptible to damage of naloxone are sometimes needed to reverse respiratory depression (Orwin et al 1976; Knape 1986; Gal 1989), because of the high afﬁ nity of buprenorphine to the mu receptor as well as the slow dissociation from the receptor. Because of its partial agonist activity and the associated Respiratory depression with the use of buprenorphine, ceiling effect in respiratory depression (Walsh et al 1995), except after the intraspinal route (Chrubasik et al transdermal buprenorphine is useful for treatment in the 1994), is very rare (Ventafridda et al 1983). It must be elderly who are more prone to respiratory depression asso- remembered that concomitant exposure to other drugs that ciated with common respiratory diseases such as chronic can induce or inhibit the enzyme may intensify the action bronchitis, emphysema, and chronic obstructive pulmonary of buprenorphine. Opioids, anesthetic agents, sedatives, disease. Downing et al (1979) studied 10 critically ill patients hypnotics, monoamine oxidase inhibitors, antidepressants, in whom intravenous buprenorphine 0.2–0.4 mg had no neuroleptics, and alcohol can intensify the CNS effects of signiﬁ cant effect on base excess values, oxygen saturation, or heart rate. It did, however, increase the arterial carbon dioxide levels and reduce respiratory rate in these patients. Disadvantages in the elderly
A large study in 3,690 cancer patients (44% of whom were To avoid opioid toxicity symptoms, buprenorphine should be Ն70 years of age) clearly showed the effectiveness and used with caution when it is being used with other drugs such safety of the transdermal buprenorphine patch in the elderly as benzodiazepines. This interaction with benzodiazepines can occur with all opioids and is related to the synergistic Clinical Interventions in Aging 2008:3(3) effect on the CNS causing sedation and respiratory Future research
depression. This effect is not due to hepatic metabolism In addition to cancer and arthritis, there are several chronic neuropathic pain syndromes that occur more commonly Lai and Teo (2006) studied 21 buprenorphine-related with advancing age. These include post-herpetic neuralgia deaths in Singapore. In 19 of these deaths buprenorphine and (Bowsher 1999), diabetes, and strokes. Long-standing benzodiazepines were being used concurrently, suggesting diabetes could lead to painful diabetic neuropathy, and that their concurrent use could be fatal. All these individuals strokes can be followed by post-stroke pain. The use of were under the age of 40 years. Therefore, benzodiazepines transdermal buprenorphine in these settings will require should be prescribed with caution in the elderly. It has been reported that intravenous use of buprenorphine combined with benzodiazepines has resulted in some deaths (Reynaud Conclusion
et al 1998). In the event of respiratory depression when Chronic pain in the elderly is a signiﬁ cant problem and transdermal buprenorphine and benzodiazepines are used the age-related metabolic, cognitive, and pharmacokinetic concurrently, the treatment would include respiratory support changes associated with advanced age make pain control with mechanical ventilation if necessary until buprenorphine in the elderly a challenge. The transdermal buprenorphine matrix allows for slow release of buprenorphine, and dam- age does not produce dose dumping, which is an added Buprenorphine and drug
advantage especially in the elderly (Budd 2003). The high dependence
incidence of coexisting diseases such as diabetes, cardio- Buprenorphone is licensed to treat drug dependence. In vascular, and neurological diseases in the elderly raises the large experience published, there are fewer deaths with concerns of drug interactions with multiple medications. In buprenorphine maintenance therapy than with methadone. If addition the elderly need special consideration for adherence a patient with cancer and opioid dependence or a history of to medication regimen and drug delivery (Priano et al 2006). drug abuse had pain, buprenorphine would be a reasonable The recently developed transdermal buprenorphine, with choice in combination with naloxone.
its unique pharmacodynamics and special matrix formula- tion, shows promise for the control of this difﬁ cult problem Use in the presence of cognitive
in the elderly. The pharmacodynamics of buprenorphine disorders
shows that it has several advantages for use in the elderly. In the elderly suffering from cognitive and motor deﬁ cits as Scientiﬁ c studies have signiﬁ cantly refuted misconcep- a result of chronic neurological diseases such as Parkinson’s tions of buprenorphine in the past, such as the inability to disease and Alzheimer’s disease, transdermal buprenorphine produce adequate analgesia because of its partial agonist will be a useful tool for the administration of drugs when effect, the ineffectiveness of other opioids to act in the pres- patients are forgetful, or unwilling or unable to swallow oral ence of buprenorphine, and the concern that if respiratory medications. Cumbersome equipment associated with the use depression occurred it could not be reversed with naloxone. of intravenous of subcutaneous infusions can also be avoided. Recent scientiﬁ c studies with buprenorphine have shown no Rate-controlled delivery through the transdermal route leads evidence of a ceiling dose of analgesia in humans but only a to constant plasma concentrations of the drug irrespective of ceiling effect for respiratory depression (Walsh et al 1995), suggesting a low abuse liability and increased safety. Its Buprenorphine is metabolized by the liver by glucuroni- mu agonist properties of long duration exist for analgesia, dation and not oxidation, and should be used in caution with sedation, euphoria, and papillary constriction. Naloxone elderly patients with hepatic disease such as cirrhosis, though has been found to reverse any respiratory depression caused glucuronidation is less affected by liver disease than is oxi- by buprenorphine (Gal 1989). The safe and effective use dation of opioids. In patients with increased temperature, of transdermal buprenorphine in the presence of renal additional monitoring may be required since increased body failure makes it an attractive choice for older individuals temperature can increase skin permeability. Conditions where who have a higher predisposition for the development of buprenorphine are contraindicated are patients with opioid renal insufﬁ ciency. In addition the low potential for drug dependence, myasthenia gravis, respiratory depression, and to drug interaction along with the beneﬁ cial effects on the immune system makes it a suitable opioid for use in the Clinical Interventions in Aging 2008:3(3) Transdermal buprenorphine for chronic pain in the elderly elderly (Griessinger et al 2005). It must be remembered, D’elia M, Patenaude J, Hamelin C, et al. 2003. No detrimental effect from chronic exposure to buprenorphine on corticosteroid-binding globulin however, that buprenorphine and transdermal buprenorphine and corticosensitive immune parameters. Clin Immunol, 109:179–87.
could be associated with sedation and the elderly should be Dahan A, Yassen A, Bijl H, et al. 2005. Comparison of the respiratory monitored carefully for this side effect. In addition buprenor- effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth, 94:825–34.
phine should be used with caution with other drugs such as Dahan A, Yassen A, Romberg R, et al. 2006. Buprenorphine induces benzodiazepines. More outcome studies are needed on the ceiling in respiratory depression but not in analgesia. Br J Anaesth, 96:627–32.
effectiveness of transdermal buprenorphine for control of Davis M, Srivastava, M. 2003. Demographics, assessment and management chronic pain associated with conditions more commonly of pain in the elderly. Drugs Aging, 20:23–57.
seen in the elderly such as diabetic neuropathy, post-stroke Downing JW, Goodwin NM, Hicks J. 1979. The respiratory depressive effects of intravenous buprenorphine in patients in an intensive care unit. S Afr Med J, 55:1023–7.
Ebert B, Andersen S, Krogsgaard-Larsen P. 1995. Ketobemidone, Disclosures
methadone and pethidine are non-competitive N-methyl-D-aspartate NMDA. antagonists in the rat cortex and spinal cord. Neurosci Lett, Neither author has any conﬂ icts of interest to declare.
Evans H, Easthope S. 2003. Transdermal buprenorphine. Drugs, References
Filitz J, Griessinger N, Sittl R, et al. 2006. Effects of intermittent hemodi- Abrahm J. 2000. Advances in pain management for older adult patients. alysis on buprenorphine and norbuprenorphine plasma concentrations Clin Geriatr Med, 16:269–311.
in chronic pain patients treated with transdermal buprenorphine. Eur Angst M, Koppert W, Pahl I, et al. 2003. Short-term infusion of the mu- opioid agonist remifentanil in humans causes hyperalgesia during Foley KM. 2003. Opioids and chronic neuropathic pain. N Engl J Med, withdrawal. Pain, 106:49–57.
Balint G. 2002. Buprenorphine treatment of patients with non-malignant Freye E, Anderson-Hillemacher A, Ritzdorf I, et al. 2007. Opioid rotation musculoskeletal diseases. Clin Rheumatol, 21(Suppl 1):S17–8.
from high-dose morphine to transdermal buprenorphine Transtec. in Balázs E, Ruszwurm A, Székely M, et al. 2008. [Old age and kidneys.]. chronic pain patients. Pain Pract, 7:123–9.
Gagliese L, Melzack R. 1997. Chronic pain in elderly people. Pain, Benedetti F, Vighetti S, Amanzio M, et al. 1998. Dose-response relation- ship of opioids in nociceptive and neuropathic postoperative pain. Gal TJ. 1989. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther, 45:66–71.
Bloms-Funke P, Gillen C, Schuettler A, et al. 2000. Agonistic effects of Gandy S, Payne R. 1986. Back pain in the elderly:updated diagnosis and the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides, management. Geriatrics, 41:59–62, 67–74.
Gomez-Flores R, Weber R. 2000. Differential effects of buprenorphine Bohme K. 2002. Buprenorphine in a transdermal therapeutic system–a new and morphine on immune and neuroendocrine functions following option. Clin Rheumatol, 21(Suppl 1):S13–6.
acute administration in the rat mesencephalon periaqueductal gray. Book S, Myrick H, Malcolm R, et al. 2007. Buprenorphine for postoperative Immunopharmacology, 48:145–56.
pain following general surgery in a buprenorphine-maintained patient. Graziotti PJ, Goucke CR. 1997. The use of oral opioids in patients with chronic non-cancer pain. Management strategies. Med J Aust, Bowsher D. 1999. The lifetime occurrence of Herpes zoster and prevalence of post-herpetic neuralgia:A retrospective survey in an elderly popula- Greenwald M, Johanson C, Moody D, et al. 2003. Effects of buprenorphine tion. Eur J Pain, 3:335–42.
maintenance dose on mu-opioid receptor availability, plasma con- Brewster D, Humphrey MJ, McLeavy MA. 1981. Biliary excretion, metabo- centrations, and antagonist blockade in heroin-dependent volunteers. lism and enterohepatic circulation of buprenorphine. Xenobiotica, Neuropsychopharmacology, 28:2000–9.
Griessinger N, Sittl R, Likar R. 2005. Transdermal buprenorphine in clinical Budd K. 2003. Buprenorphine and the transdermal system:the ideal match in practice—a post-marketing surveillance study in 13,179 patients. Curr pain management. Int J Clin Pract, (Suppl):9–14; discussion 23–4.
Budd K, Collett BJ. 2003. Old dog–new ma.trix. Br J Anaesth, 90:722–4.
Grond S, Radbruch L, Lehmann KA. 2000. Clinical pharmacokinetics of Casten RJ, Parmelee PA, Kleban MH, et al. 1995. The relationships among transdermal opioids:focus on transdermal fentanyl. Clin Pharmaco- anxiety, depression, and pain in a geriatric institutionalized sample. Hand C, Sear J, Uppington J, et al. 1990. Buprenorphine disposition in Chrubasik J, Martin E, Chrubasik S, et al. 1994. Epidural buprenorphine. patients with renal impairment:single and continuous dosing, with How safe is “safe”. Acta Anaesthesiol Scand, 38:525–6.
special reference to metabolites. Br J Anaesth, 64:276–82.
Clarot F, Proust B, Vaz E, et al. 2003. Tramadol-benzodiazepines and Heel RC, Brogden RN, Speight TM, et al. 1979. Buprenorphine:a review buprenorphine-benzodiazepines:two potentially fatal cocktails? J Clin of its pharmacological properties and therapeutic efﬁ cacy. Drugs, Cleeland CS, Gonin R, Hatﬁ eld AK, et al. 1994. Pain and its treatment in Helme RD, Katz B, Gibson S, et al. 1989. Can psychometric tools be outpatients with metastatic cancer. N Engl J Med, 330:592–6.
used to analyse pain in a geriatric population? Clin Exp Neurol, Cone EJ, Gorodetzky CW, Yousefnejad D, et al. 1984. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos, 12:577–81.
Ibrahim R, Wilson J, Thorsb Y, et al. 2000. Effect of buprenorphine Crook J, Rideout E, Browne G. 1984. The prevalence of pain complaints on CYP3A activity in rat and human liver microsomes. Life Sci, in a general population. Pain, 18:299–314.
Célèrier E, Rivat C, Jun Y, et al. 2000. Long-lasting hyperalgesia induced Iribarne C, Picart D, Dréano Y, et al. 1998. In vitro interactions between by fentanyl in rats:preventive effect of ketamine. Anesthesiology, ﬂ uoxetine or ﬂ uvoxamine and methadone or buprenorphine. Fundam Clinical Interventions in Aging 2008:3(3) Jasinski DR, Pevnick JS, Grifﬁ th JD. 1978. Human pharmacology and abuse Priano L, Gasco MR, Mauro A. 2006. Transdermal treatment options for potential of the analgesic buprenorphine:a potential agent for treating neurological disorders:impact on the elderly. Drugs Aging, 23:357–75.
narcotic addiction. Arch Gen Psychiatry, 35:501–16.
Reynaud M, Tracqui A, Petit G, et al. 1998. Six deaths linked to misuse Jensen M, Foster D, Upton R, et al. 2007. Population pharmacokinetics of of buprenorphine-benzodiazepine combinations. Am J Psychiatry, buprenorphine following a two-stage intravenous infusion in healthy volunteers. Eur J Clin Pharmacol, 63:1153–9.
Rowbotham MC, Twilling L, Davies PS, et al. 2003. Oral opioid therapy Jiang R, Roberts MS, Prankerd RJ, et al. 1997. Percutaneous absorption of for chronic peripheral and central neuropathic pain. N Engl J Med, sunscreen agents from liquid parafﬁ n:self-association of octyl salicylate and effects on skin ﬂ ux. J Pharm Sci, 86:791–6.
Shah F, Halbe A, Panchal I, et al. 2003. Improvement in postoperative Johnson RE, Fudala PJ, Payne R. 2005. Buprenorphine:considerations for pain relief by the addition of midazolam to an intrathecal injection of pain management. J Pain Symptom Manage, 29:297–326.
buprenorphine and bupivacaine. Eur J Anaesthesiol, 20:904–10.
Kintz P. 2002. A new series of 13 buprenorphine-related deaths. Clin Simonnet G. 2005. Opioids: from analgesia to anti-hyperalgesia? Pain, Kisely S, Tweddle D, Pugh EW. 1992. Dementia presenting with sore eyes. Simonnet G, Rivat C. 2003. Opioid-induced hyperalgesia: abnormal or Br J Psychiatry, 161:120–1.
normal pain? Neuroreport, 14:1–7.
Knape J. 1986. Early respiratory depression resistant to naloxone following Simpson KH. 2002. Individual choice of opioids and formulations:strategies epidural buprenorphine. Anesthesiology, 64:382–4.
to achieve the optimum for the patient. Clin Rheumatol, 21 (Suppl 1): Koppert W, Ihmsen H, Körber N, et al. 2005. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain Sittl R. 2006. Transdermal buprenorphine in cancer pain and palliative care. Palliat Med, 20 (Suppl 1):s25–30.
Kouya PF, Hao JX, Xu XJ. 2002. Buprenorphine alleviates neuropathic Sittl R, Griessinger N, Likar R. 2003. Analgesic efﬁ cacy and tolerability pain-like behaviors in rats after spinal cord and peripheral nerve injury. of transdermal buprenorphine in patients with inadequately controlled Eur J Pharmacol, 450:49–53.
chronic pain related to cancer and other disorders: a multicenter, random- Lai SH, Teo CE. 2006. Buprenorphine-associated deaths in Singapore. Ann ized, double-blind, placebo-controlled trial. Clin Ther, 25:150–68.
Acad Med Singapore, 35:508–11.
Sittl R, Nuijten M, Nautrup B. 2005. Changes in the prescribed daily doses Likar R, Griessinger N, Sadjak A, et al. 2003. [Transdermal buprenorphine of transdermal fentanyl and transdermal buprenorphine during treatment for treatment of chronic tumor and non-tumor pain]. Wien Med of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study. Clin Ther, 27:1022–31.
Likar R, Kayser H, Sittl R. 2006. Long-term management of chronic pain Sittl R, Nuijten M, Nautrup BP. 2006. Patterns of dosage changes with with transdermal buprenorphine:a multicenter, open-label, follow- transdermal buprenorphine and transdermal fentanyl for the treatment up study in patients from three short-term clinical trials. Clin Ther, of noncancer and cancer pain: a retrospective data analysis in Germany. Likar R, Sittl R. 2005. Transdermal buprenorphine for treating nociceptive Sorge J Sittl R. 2004. Transdermal buprenorphine in the treatment of chronic and neuropathic pain:four case studies. Anesth Analg, 100:781–5.
pain: results of a phase III, multicenter, randomized, double-blind, Mao J, Price DD, Mayer DJ. 1995. Experimental mononeuropathy reduces placebo-controlled study. Clin Ther, 26:1808–20.
the antinociceptive effects of morphine:implications for common intra- Summerﬁ eld R, Allen M, Moore R, et al. 1985. Buprenorphine in end stage cellular mechanisms involved in morphine tolerance and neuropathic renal failure. Anaesthesia, 40:914.
Thompson J, Bower S, Liddle A, et al. 1998. Perioperative pharmacokinetics McQuay HJ. 2002. Neuropathic pain:evidence matters. Eur J Pain, 6 of transdermal fentanyl in elderly and young adult patients. Br J Muriel C, Failde I, Mico JA, et al. 2005. Effectiveness and tolerability of Umehara K, Shimokawa Y, Miyamoto G. 2002. Inhibition of human drug the buprenorphine transdermal system in patients with moderate to metabolizing cytochrome P450 by buprenorphine. Biol Pharm Bull, severe chronic pain:a multicenter, open-label, uncontrolled, prospective, observational clinical study. Clin Ther, 27:451–62.
Vadivelu N, Hines RL. 2007. Buprenorphine: a unique opioid with broad Negus SS, Mello NK, Linsenmayer DC, et al. 2002. Kappa opioid antago- clinical applications. J Opioid Manag, 3:49–58.
nist effects of the novel kappa antagonist 5’-guanidinonaltrindole Ventafridda V, De Conno F, Guarise G, et al. 1983. Chronic analgesic study GNTI. in an assay of schedule-controlled behavior in rhesus monkeys. on buprenorphine action in cancer pain. Comparison with pentazocine. Psychopharmacology Berl, 163:412–9.
Ohtani M, Kotaki H, Nishitateno K, et al. 1997. Kinetics of respiratory Walsh SL, Preston KL, Bigelow GE, et al. 1995. Acute administration depression in rats induced by buprenorphine and its metabolite, of buprenorphine in humans:partial agonist and blockade effects. norbuprenorphine. J Pharmacol Exp Ther, 281:428–33.
J Pharmacol Exp Ther, 274:361–72.
Omote K, Ohmori H, Kawamata M, et al. 1995. Intrathecal buprenorphine Walsh SL, Preston KL, Stitzer ML, et al. 1994. Clinical pharmacology of in the treatment of phantom limb pain. Anesth Analg, 80:1030–2.
buprenorphine:ceiling effects at high doses. Clin Pharmacol Ther, Orwin J, Orwin J, Price M. 1976. A double blind comparison of buprenorphine and morphine in conscious subjects following administration by the Woo J, Ho SC, Lau J, et al. 1994. Musculoskeletal complaints and associated intramuscular route. Acta Anaesthesiol Belg, 27:171–81.
consequences in elderly Chinese aged 70 years and over. J Rheumatol, Pace MC, Passavanti MB, Grella E, et al. 2007. Buprenorphine in long-term control of chronic pain in cancer patients. Front Biosci, 12:1291–9.
Yassen A, Olofsen E, Dahan A, et al. 2005. Pharmacokinetic-pharmaco- Parikh A. 2007. Principles of geriatric pharmacology. J Indian Med Assoc, dynamic modeling of the antinociceptive effect of buprenorphine and fentanyl in rats: role of receptor equilibration kinetics. J Pharmacol Pavelka K, Le Loet X, Bjorneboe O, et al. 2004. Beneﬁ ts of transdermal fentanyl in patients with rheumatoid arthritis or with osteoarthritis of Zaki PA, Keith DE, Jr, Brine GA, et al. 2000. Ligand-induced changes in the knee or hip:an open-label study to assess pain control. Curr Med surface mu-opioid receptor number:relationship to G protein activation? J Pharmacol Exp Ther, 292:1127–34.
Pepe GJ, Waddell BJ, Stahl SJ, et al. 1988. The regulation of transplacen- Zhang Y, Du LN, Wu GC, et al. 1998. Modulation of intrathecal morphine- tal cortisol-cortisone metabolism by estrogen in pregnant baboons. induced immunosuppression by microinjection of naloxone into periaqueductal gray. Zhongguo Yao Li Xue Bao, 19:519–22.
Clinical Interventions in Aging 2008:3(3)
A two-day workshop designed to equip unionists with the skills they need to read and interpret body language in negotiations What does your opponent see in your The Five Underlying Facts You Must The Three Underpinnings of "Win/Win" The Three Stages of Every Negotiation First impressions are lasting impressions Our posture, what it communi