Management 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 Introduction 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
with resultant difﬁ culty in applying the conservative and
interventional therapies in these patients. of buprenorphine
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).
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
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
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.
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
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
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
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
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.
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