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Perioperative Management of Opioid-

tolerant Patients
GK Simpson MBChB(Hons) MRCP FRCA FFPMRCA; M Jackson MBChB FRCA
FFPMANZCA FFPMRCA

BJA Education. 2017;17(4):124-128.

Abstract and Introduction

Introduction

The assessment and treatment of opioid-tolerant patients in the perioperative and postoperative
period can be challenging. Acute pain management can often be inadequate due to a number of
factors. Compared with opioid-naive patients, opioid-tolerant patients will typically generate a
greater workload for medical and nursing staff. Opioid tolerant patients express higher rest and
dynamic pain scores, and two to three times greater opioid use via patient-controlled analgesia
(PCA). They require more frequent consultations and prescription alterations.[1] Medical and
nursing staff may be unaccustomed to managing such patients and may be apprehensive in
prescribing or administering large doses of opioids because of a fear of causing harm. Under-
treatment of pain may result in opioid-seeking behaviour with the patient perceived as
'manipulative' and 'non-cooperative'. This can have a negative impact on the doctorpatient
relationship and overall patient care.

Therefore the pain management plan for opioid tolerant patients requires careful consideration in
the perioperative period in order to (i) prevent opioid withdrawal, (ii) provide effective analgesia,
and (iii) to ensure continuity of care in the community after discharge from hospital. This review
considers the various strategies that can be used in such settings.

The Use of Strong Opioids in the Community

Opioids are prescribed to treat pain from a variety of causes, including chronic non-cancer pain,
cancer pain, acute pain, and as substitution therapy in those with a substance abuse disorder. A
discussion regarding the evidence for the use of long-term strong opioids is outside the scope of
this article; however, it is important to be aware that treatment with strong opioids is often
unwittingly continued, even in the absence of a clinically meaningful benefit. There is evidence
to suggest that two-thirds of patients receiving a dose of >120 mg day1 oral morphine
equivalent, or those treated for a duration of >3 months, are likely to continue their medication
for years.[2] The Royal College of Anaesthetists' has recently produced an online resource to
increase awareness and support safe opioid prescribing.[3]

In addition, there has been a dramatic increase in opioid prescribing over the last two decades,
and this has been paralleled by an increase in adverse events. In the USA, unintentional deaths
from drugs more than tripled between 1990 and 2002 and the rate of increase in deaths generally
follows the increase in pharmacy sales of strong opioids.[4] The risk of an adverse event is higher
among patients prescribed >50 mg oral morphine equivalent per day. Patients receiving > 50 or
>100 mg day1 have a 3.7- and 8.9-fold increase in risk of an overdose compared with patients
receiving doses <20 mg day1.[5]

It is therefore of paramount importance to formulate and communicate a plan for onward-care

after discharge from hospital. This may typically involve a discussion with the patient's GP and a
carefully documented discharge letter highlighting the importance of reducing and stopping
treatment if it is ineffective or no longer required. Some patients may already have agreed plans
in place with their GP (e.g. weekly or daily prescription). Either way, a discussion with the
patient, GP, and pharmacist can encourage a consistent and safer system of working.

Assessment and Monitoring

There is no doubt that assessment of pain can be challenging and opioid tolerant patients
consistently report higher pain scores. When assessing the overall effectiveness of pain
management, it is important to consider other important factors. These include the presence of
opioid-related side-effects, signs of opioid withdrawal, patient expectations, patient satisfaction,
mood, and levels of physical function (e.g. ability to cough, deep breathe, and engage with
physiotherapists and other services).

Acute Pain Management Plan

The early identification of complex patients by surgeons and preoperative assessment staff is
highly recommended and can facilitate forward planning and ample time to involve the
experience of others (e.g. anaesthetists, pain specialists, psychologist, GP, occupational
therapists and physiotherapists etc).

It is important to adhere to a clear and well-documented multi-disciplinary management plan that

has been created with the involvement of the patient. Opioid-sparing techniques may be of
particular importance in patients taking strong opioids.

Opioid-sparing Techniques

Regularly prescribed paracetamol, non-steroidal anti-inflammatory drugs, or COX-2s

should be used unless contraindicated.[69]
The use of local anaesthetic techniques including wound infiltration, regional, or
neuroaxial block should be used where possible to improve postoperative analgesia and
decrease immediate-release (IR) opioid requirement. Local anaesthetic catheters can
prolong the benefits of regional anaesthesia well into the postoperative period.[69]
 Ketamine is recommended in the acute pain management of opioid-tolerant patients as it
has been shown to reduce postoperative opioid use and pain scores. Activation of the N-
methyl-d-aspartate (NMDA) receptor is believed to be one of the mechanisms for the
development of opioid tolerance and opioid-induced hyperalgesia (OIH). Ketamine is a
non-competitive antagonist of the NMDA receptor and can attenuate both of these
phenomena. Ketamine administered in a low dose as a continuous i.v. or subcutaneous
infusion for 13 days can be a useful adjunct for opioid-tolerant patients.[68] There are a
number of dosing regimes available; however, the authors recommend a starting dose of
100200 mg 24 h1, using a mixture of 200 mg ketamine and 5 mg midazolam made up
to a total volume of 48 ml with normal saline and a rate of infusion of 12 ml h1.
The use of gabapentinoids (e.g. gabapentin/pregabalin) in acute pain has become more
prevalent, particularly in enhanced recovery protocols. Initial studies indicated improved
postoperative pain relief and reduced opioid use, but this was traded against an increased
risk of sedation. Lunn and colleagues[10] published a study in 2015 of gabapentin as part
of an enhanced recovery protocol for total knee arthroplasty. Gabapentin conferred no
benefit when used with other multimodal analgesia and produced dose-related side-
effects that compromised recovery in some patients. The benefit of gabapentinoids in the
treatment of opioid-nave patients for routine acute pain management is uncertain.
However, gabapentinoids may have a role in opioid-tolerant patients as an opioid-sparing
adjunct. The authors recommend their use in patients who, despite maximizing other
opioid-sparing techniques and using appropriate doses of opioids, still have poorly
managed pain. There is little clinical evidence to support their use in this group of
patients or to guide their dosing regime. The authors use postoperative doses similar to
that for the initial management of neuropathic pain such as gabapaentin 100300 mg
t.d.s. and pregabalin 5075 mg b.d., titrated according to efficacy and side-effects.[1,9]
Again, a mechanism should be in place to ensure a review of medication in the
community as gabapentinoids are also known to be abused.
The use of i.v. lidocaine infusions can be useful in some situations and is the subject of a
review[11] in this journal.

Prevention of Withdrawal

Withdrawal symptoms occur if a drug is suddenly stopped, reversed, reduced too quickly, or fails
to reach its intended site of action. It is generally recommended that the patient's baseline opioid
(usually a sustained-release form) is continued in the postoperative period and that acute post-
surgical pain is managed with the addition of appropriate doses of IR opioids. We would
recommend continuing transdermal opioids at their baseline dose, although caution must be
taken with the positioning of the patch. Direct heat applied to the patch, for example, via
perioperative warming devices may enhance drug administration, whereas the use of a patch over
an area of poor-perfusion or reduced temperature can reduce drug delivery.[12] The use of a
buprenorphine patch (up to 70 g h1) is unlikely to interfere with the use of full opioid agonists
for acute pain management and these should also be continued in the perioperative period.1
However, the management of patients taking high-dose sublingual (SL) buprenorphine as a
substitution therapy for drug addiction can be problematic, and is discussed later.
It is important to remember that parenteral replacement may be needed if a patient taking oral
opioids is unable to take medication orally or is not absorbing from the gut ().

Table 1. Converting to an equivalent i.v. dose of morphine

An opioid-tolerant patient taking 200 mg of sustained-release morphine twice daily

requires an emergency laparotomy and is expected to be nil by mouth postoperatively.
To prevent withdrawal, maintain the usual oral 24 h opioid dose of 400 mg
Convert the dose of oral morphine to i.v. morphine. Ratio between 3 and 2:1
Using a 3:1 conversion ratio
Total i.v. dose over 24 h=133 mg
Background infusion (133 mg 24 h1)=5.5 mg h1
Bolus dose: start at 50% of the hourly background rate=2.53 mg (with 5 min lockout)

Additional Opioids

In the postoperative period, opioid-tolerant patients may require a greater amount of IR oral
opioids than is usually expected. Traditionally, the 'as required' (p.r.n.) dose is calculated based
on the cumulative oral opioid dose given in the preceding 24 h with one-sixth of the total dose
prescribed 4 hourly. Nevertheless, the dose of IR opioid required for analgesia may not correlate
so easily, and starting with standard doses may be appropriate with regular assessment and
titration depending on patient response.

I.V. PCA is in widespread use for the management of acute pain. It allows individual dose
titration and reduces workload for staff. It can be difficult to identify the optimal starting regime
in opioid-tolerant patients, but one method is to base the size of the bolus dose on the patient's
usual 24 h opioid requirement ().

Table 1. Converting to an equivalent i.v. dose of morphine

An opioid-tolerant patient taking 200 mg of sustained-release morphine twice daily

requires an emergency laparotomy and is expected to be nil by mouth postoperatively.
To prevent withdrawal, maintain the usual oral 24 h opioid dose of 400 mg
Convert the dose of oral morphine to i.v. morphine. Ratio between 3 and 2:1
Using a 3:1 conversion ratio
Total i.v. dose over 24 h=133 mg
Background infusion (133 mg 24 h1)=5.5 mg h1
Bolus dose: start at 50% of the hourly background rate=2.53 mg (with 5 min lockout)

Opioid Rotation

Switching from one opioid to another (opioid rotation) is a common practice in chronic pain and
cancer pain management. It is a useful option if patients have developed intolerable side-effects
or inadequate analgesia, despite escalating doses. Although patients also develop tolerance to
side-effects (e.g. itching, nausea, and sedation), the rate of development is non-uniform and
unpredictable. If a patient develops tolerance to analgesia at a greater rate than to side-effects,
they are often unable to tolerate the increased doses required for analgesia. Rotation can lead to
both a reduction in side-effects and an improvement in pain relief because an individual may
respond differently to an alternative opioid due to the phenomenon of incomplete cross-
tolerance. Cross-tolerance is the observation that exposure to a particular drug (e.g. opioid)
results in tolerance to the effects of structurally similar drugs in the same class (e.g. other
opioids). When cross-tolerance is incomplete, patients may not have tolerance to the alternative
drug.

Equianalgesic tables (Fig. 1) are commonly used to help calculate the equivalent dose of an
alternative opioid, but should be used cautiously. They are based on small studies, single doses,
and healthy opioid-nave volunteers. They therefore do not reflect complex and heterogeneous
clinical situations.[13] When performing an opioid rotation, it is recommended to reduce the
calculated equianalgesic dose by 3050% because of the possibility of incomplete cross-
tolerance. Patients can use additional IR opioids if necessary.
Figure 1.

Approximate opioid equivalence.

As an example of an opioid rotation in the perioperative setting, consider a patient whom is

usually prescribed methadone, and will be nil by mouth after an emergency laparotomy. It is
important to replace the background opioid requirement to prevent opioid withdrawal, and this
might be achieved via the use of a fentanyl or morphine PCA ().

Table 2. Opioid rotation from oral methadone to i.v. morphine

An emergency laparotomy is required in a patient taking 100 mg of oral methadone and

whom will be nil by mouth after operation
As the patient is unable to take oral methadone, this is converted to a suitable i.v. dose to
prevent withdrawal
Conversion ratio for oral methadone to oral morphine 1:2 or 3
Using a 1:3 ratio 100 mg of oral methadone is equivalent to 300 mg of oral morphine
300 mg of oral morphine is equivalent to a 100 mg of i.v. morphine
Due to incomplete cross-tolerance between opioids, a 50% reduction in the calculated
equianalgesic dose is recommended
The dose of i.v. morphine required to prevent withdrawal over 24 h is 50 mg
This can be provided via PCA with either
a. an increased bolus dose of between 1.5 and 2 mg or
b. a standard PCA bolus of 1 mg but with a background infusion of 2 mg h1

Converting From I.V. to Oral Opioid

Patients will need to be converted back to oral medication as their clinical situation allows. A
typical strategy for returning to oral medication is to identify the i.v. opioid consumption in the
previous 24 h and convert this to an equivalent oral dose. Fifty per cent of this oral equivalent
dose is then given in a sustained-release form, and one-sixth of the equivalent dose is prescribed
as an IR preparation every 4 h ().

Table 3. Converting from i.v. to oral opioid

i. 60 mg i.v. morphine 24 h1=120180 mg oral morphine

ii. 50% of this dose=6090 mg/day and therefore=3045 mg morphine sulphate (MST) b.d.
iii. PRN=1/6 of 120180 mg=2030 mg p.r.n. 4 hourly

Opioid Tolerance and OIH

Opioid tolerance (for definitions, see ) is frequently encountered in patients taking long-term
opioids. In order to improve analgesia either an increase in the opioid dose or an opioid rotation
could be considered. On the contrary, OIH is a paradoxical phenomenon whereby an opioid can
induce a pronociceptive state in the central nervous system. OIH was first observed in patients
taking methadone for opioid addiction. The underlying mechanism is complex but likely to
involve a combination of glial cell activation, NMDA receptor activation, glutaminergic
activation, and alterations in opioid intracellular signalling.[14] As a result, the treatment of OIH
necessitates an opioid dose reduction. This can be a difficult concept to understand for a patient
who is in pain, as well as for their doctor. Nevertheless, it is often difficult to clinically
distinguish between opioid tolerance, OIH, and progression of the underlying disease process.
Importantly, patients with OIH may report more diffuse and widespread pain and 'sensitivity'
which does not respond to an increase in the dose of opioid.

Table 4. Definitions

Tolerance Predictable and physiological

Increased dose required for the same effect

Physical Predicable and physiological

dependence Stop, reverse, reduce = withdrawal syndrome

Addiction Unpredictable effect of drug (a disease)

Aberrant drug-seeking/drug-taking behaviour
Despite risks of physical, social, and psychological harm

Pseudo-addiction Drug seeking due to under-treatment of pain

Resolves when pain relief adequate
Based on one 1989 case report,15 and definition never subjected to
serious study

Opioid-induced A state of nociceptive sensitization secondary to exposure to

hyperalgesia opioids. Often more diffuse and widespread pattern of pain

It was previously thought that OIH only occurred in patients on long-term opioids, but both
tolerance and OIH have been associated with short-term use of high potency opioids, for
example, remifentanil. However, this association has not been fully established and studies are
conflicting.[1]

Substance Abuse and Substitution Therapy

The prevalence of problem drug use is ~1 in 100 people between the ages of 1564, and the use
of i.v. drugs is ~1 in 300.[15] Substitution therapy aims to reduce harm from problem drug use,
provide stability, prevent withdrawal, and reduce preoccupation and craving. Methadone is
typically started (specialist only) at a dose of between 10 and 40 mg, and increased in 10 mg
increments (max 30 mg week1) to a typical maintenance dose of between 60 and 120 mg day1.
Buprenorphine as a maintenance therapy is typically administered as an SL dose between 0.8 and
4 mg (max 32 mg) with typical maintenance doses of between 12 and 24 mg.[15]

Methadone

Methadone is a -agonist as well as an NMDA-antagonist and monoamine reuptake inhibitor. It

is metabolized in the liver to inactive metabolites by CYP3A4, which is saturated at low
concentrations, and itself also weakly inhibited by methadone. Patients who are receiving
methadone maintenance therapy should be managed as any other opioid-tolerant patient. If able,
they should continue taking their usual oral methadone in the perioperative and postoperative
periods. Additional IR opioids should be used to manage acute pain if appropriate. If patients
need to be nil by mouth or there is concern about gastrointestinal absorption, there should be
consideration of a rotation to an i.v. fentanyl or morphine PCA to prevent withdrawal and
provide analgesia ().

Table 4. Definitions

Tolerance Predictable and physiological

Increased dose required for the same effect

Physical Predicable and physiological

dependence Stop, reverse, reduce = withdrawal syndrome

Addiction Unpredictable effect of drug (a disease)

Aberrant drug-seeking/drug-taking behaviour
Despite risks of physical, social, and psychological harm

Pseudo-addiction Drug seeking due to under-treatment of pain

Resolves when pain relief adequate
Based on one 1989 case report,15 and definition never subjected to
serious study

Opioid-induced A state of nociceptive sensitization secondary to exposure to

hyperalgesia opioids. Often more diffuse and widespread pattern of pain

Buprenorphine

Buprenorphine is a partial agonist at -receptors, and an antagonist at and receptors. It has a

high affinity for opioid receptors, and dissociates slowly resulting in an extended duration of
action. It is used in addiction medicine to suppress opioid withdrawal and craving for 2448 h,
and is less sedating and euphoric. There is a theoretical concern that the use of high-dose SL
buprenorphine will antagonize the effect of a full agonist, thereby leading to either opioid
withdrawal (if the patient is already taking high-dose full agonists) or analgesic failure.

There are very few reports describing perioperative pain management of patients administered
high-dose SL buprenorphine. Strategies in this situation have included continuing the usual dose
of buprenorphine and either (i) providing additional full opioid agonists or (ii) prescribing
supplemental doses of buprenorphine. An alternative strategy involves rotating to a full agonist
before surgery such as methadone.

In one series, five patients having seven major operations were taking 224 mg buprenorphine
per day. Pain control was reported to be adequate with oral or i.v. full agonists.[16] In a
randomized controlled trial comparing PCA morphine, with or without the addition of
buprenorphine, there was no detrimental effect on analgesia with the addition of
buprenorphine.[17] Successful postoperative pain management has been reported with additional
doses of buprenorphine. In one case report, a baseline of 24/6 mg buprenorphine/naloxone was
supplemented by additional 2/0.5 mg as required, reaching a maximum daily dose of 72/18 mg.
The patient was able to self-titrate back to the original starting dose by 11 days.[18]

The authors currently recommend continuing the patients usual dose of SL buprenorphine,
maximizing the use of opioid-sparing adjuncts, and using conventional full opioid agonists to
treat acute pain. The doses of IR opioid required for analgesia may be appreciably higher than
one would expect for other opioid-tolerant patients and in view of this, it may be advisable to
monitor the patient in a high dependency environment.

Naltrexone

Naltrexone is primarily used in patients whom are highly motivated to remain abstinent from
alcohol or a substance abuse disorder. It is a long-acting competitive opioid antagonist with a
duration of action of ~4872 h. Chronic use results in increased sensitivity to morphine-induced
analgesia and a doubling of brain - and -opioid receptors, which may return to baseline in ~6
days post-treatment.[19] It is recommended to stop naltrexone 72 h prior to surgery, and it is
important to note that although patients may be resistant to opioids while taking naltrexone, they
may then become extremely opioid sensitive once stopping it. It is therefore imperative to
maximize opioid-sparing strategies (e.g. regional anaesthesia), and consider managing the patient
in a high dependency setting in the postoperative period, to ensure appropriate monitoring of
treatment.

Summary and Conclusion

The number of patients who are receiving long-term opioid therapy has increased dramatically,
and the provision of analgesia in the perioperative period can be challenging. Fundamental
aspects of management include continuing baseline opioid requirements and maximizing other
opioid-sparing techniques. Patients on substitution therapy for substance abuse disorders can
pose unique challenges. A multi-disciplinary and multimodal approach to analgesia is essential,
as well as ensuring there is a continuing plan in place for onward care in the community, to
appropriately manage strong opioids or other adjuvants analgesics after discharge.

Sidebar

Key Points

Perioperative pain management for opioid-tolerant patients can be challenging.

Patients taking >100 mg oral morphine equivalent/day have a nine-fold increased risk of
inadvertent overdose or adverse events compared to those taking <20 mg/day.
Multi-disciplinary communication, planning, and multi-modal pain management
strategies are essential to facilitate the best possible outcomes.
Opioid tolerance and opioid-induced hyperalgesia are complex neurobiological
phenomena involving multiple cell signalling pathways.
Patients treated with naltrexone for a substance abuse disorder may have an increased
sensitivity to opioid receptor agonists after discontinuing the drug.

References

1. Roberts L. Chapter 30: the opioid tolerant patient, including those with a substance abuse
disorder. In: Macintyre PE, Walker S, Rowbotham D, eds. Clinical Pain Management,
Acute Pain, 2nd Edn. London, UK: Hodder Arnold, 2008; 53956
2. Martin BC, Fan M-Y, Edlund MJ, DeVries A, Braden JB, Sullivan MD. Long-term
chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med
2011; 26: 14507
3. Available from https://www.fpm.ac.uk/faculty-of-painmedicine/opioids-aware (accessed
6 April 2016)
4. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United
States. Pharmacoepidemiol Drug Saf 2006; 15: 61827
5. Dunn KM, Saunders KW, Rutter CM et al. Opioid prescriptions for chronic pain and
overdose: a cohort study. Ann Intern Med 2010; 152: 8592
6. The opioid tolerant patient. In: Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker
SM; APM:SE Working Group of the Australian and New Zealand College of
Anaesthetists and Faculty of Pain Medicine, Acute Pain Management: Scientific
Evidence (3rd edition), ANZCA & FPM, Melbourne 2010;42631
7. The patient with an addiction disorder. In: Macintyre PE, Schug SA, Scott DA, Visser EJ,
Walker SM; APM: SE Working Group of the Australian and New Zealand College of
Anaesthetists and Faculty of Pain Medicine, Acute Pain Management: Scientific
Evidence (3rd edition), ANZCA & FPM, Melbourne, 2010; 4337
8. Ramaswamy S, Wilson J, Colvin L. Non-opioid-based adjuvant analgesia in
perioperative care. Contin Educ Anaesth Crit Care Pain 2013; 13: 1527
9. Huxtable CA, Roberts LJ, Somogyi AA, MacIntyre PE. Acute pain management in
opioid-tolerant patients: a growing challenge. Anaesth Intensive Care 2011; 39: 80423
10. Lunn TH, Husted H, Laursen MB, Hansen LT, Kehlet H. Analgesic and sedative effects
of perioperative gabapentin in total knee arthroplasty: a randomized, double-blind,
placebo-controlled dose-finding study. Pain 2015; 156: 243848
 11. Eipe N, Gupta S, Penning J. Intravenous lidocaine for acute pain: an evidence-based
clinical update. BJA Education 2016; 16: 2928
12. Margetts L, Sawyer S. Transdermal drug delivery: principles and opioid therapy. Contin
Educ Anaesth Crit Care Pain 2007; 7: 1716
13. Natusch D. Equianalgesic doses of opioidstheir use in clinical practice. Br J Pain
2012; 6: 436
14. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of
opioid-induced hyperalgesia. Pain Physician 2011; 14: 14561
15. Weissman DE, Haddox Jd. Opioid pseudoaddiction - an iatrogenic syndrome. Pain 1989;
36: 3636
16. Available from http://www.nice.org.uk/guidance/ta114 (accessed 29 October 2015)
17. Kornfeld H, Manfredi L. Effectiveness of full agonist opioids in patients stabilized on
buprenorphine undergoing major surgery: a case series. Am J Ther 2010; 17: 5238
18. Oifa S, Sydoruk T, White I et al. Effects of intravenous patient-controlled analgesia with
buprenorphine and morphine alone and in combination during the first 12 postoperative
hours: a randomized, double-blind, four-arm trial in adults undergoing abdominal
surgery. Clin Ther 2009; 31: 52741
19. Book SW, Myrick H, Malcolm R, Strain EC. Buprenorphine for postoperative pain
following general surgery in a buprenorphine-maintained patient. Am J Psychiatry 2007;
164: 979
20. Tempel A, Gardner EL, Zukin RS. Neurochemical and functional correlates of
naltrexone-induced opiate receptor upregulation. J Pharmacol Exp Ther 1985; 232: 439

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BJA Education. 2017;17(4):124-128. 2017 Oxford University Press

Copyright 2007 The Board of Management and Trustees of the British Journal of Anaesthesia.
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