Managing acute pain in opioid tolerant patients.
Abstract: Managing acute pain in opioid tolerant patients can be a significant challenge. This article will provide an overview of the terminology used when managing acute pain in these patients. This understanding is essential to ensure adequate pain relief while avoiding opioid withdrawal. It is also crucial that these patients are identified and that sufficient peri- and postoperative pain management plans are formulated. This article will present an overview of the terms tolerance, physical dependence and addiction. The literature on the management of acute pain in opioid tolerant patients will be considered. Finally an audit that explores and compares the practises of a group of London hospitals, with regard to managing postsurgical pain in opioid-dependent patients will be discussed.

KEYWORDS Opioid tolerance / Opioid withdrawal / Patient controlled analgesia / Postoperative pain
Author: Bourne, Nicola
Pub Date: 11/01/2008
Publication: Name: Journal of Perioperative Practice Publisher: Association for Perioperative Practice Audience: Academic Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2008 Association for Perioperative Practice ISSN: 1750-4589
Issue: Date: Nov, 2008 Source Volume: 18 Source Issue: 11
Accession Number: 200343272
Full Text: Introduction

Opioids are widely used in the management of moderate to severe cancer pain as well as for chronic and acute pain (South & Smith 2001). Exposure to opioids can lead to the development of opioid tolerance and the occurrence of opioid induced pain sensitivity (hyperalgesia). The effects of these two phenomena can markedly reduce opioid analgesic efficacy, resulting in significant challenges when managing postoperative pain in this group of patients (Chang et al 2007). There are three main groups of opioid-dependent patients:

* Patients with chronic pain (treated with therapeutic opioids).

* Patients with cancer pain (treated with therapeutic opioids).

* Patients with a substance abuse either related to recreational drug use or on an opioid maintenance programme (ANZCA 2005).

For patients with a history of opioid tolerance to receive appropriate pain management it is of vital importance that clinicians have an understanding of the terminology used. Tolerance is a pharmacological adaptation to the exposure of a drug which results in a reduced response to the effect of the drug or an increased amount of drug needed to maintain the original effect (Collett 1998, Mitra & Sinatra 2004). Tolerance develops to the opioid effects of analgesia, euphoria, sedation, respiratory depression and nausea, but not to miosis or constipation (Mitra & Sinatra 2004). In brief, tolerance is characterised by neuroadaptive changes that result in desensitisation at the receptor level after long term or repeated exposure to opioids. This involves a decrease in the amount of opioid receptors available (down-regulation) and the uncoupling of opioid receptors from G proteins. The activation of N-methyl-D-asparate (NMDA) receptors by opioids may also play a part in opioid tolerance and increased pain sensitivity (Mitra & Sinatra 2004). Physical dependence is defined as a physiological adaptation to a drug which may result in physical withdrawal syndrome if the drug is abruptly stopped, reduced or reversed. This results in unpleasant and unwanted side effects (See Table 1) (Collett 1998, ANZCA 2005).

Lewis and Williams (2005) propose that opioid dependence and physical withdrawal can potentially be a problem for patients who have been on either high doses of weak opioids (for example, tramadol and codeine) or strong opioids (for example, morphine or fentanyl) for more than two weeks. Addiction is defined as 'a chronic disorder characterised by the compulsive use of a substance resulting in physical, psychological or social harm to the user and continued use despite that harm' (Collett 1998) (see Table 2).

Opioid tolerant patients have been shown to be fairly pain intolerant and have shown increased sensitivity to cold pressor and thermal testing (Doverty et al 2001). Consequently, patients with opioid tolerance are at risk of their pain being underestimated and under treated (Mehta & Langford 2006). It is therefore important that an acute pain management plan is identified for these patients. This should include the following goals:

* Identification of those patients at risk of opioid tolerance.

* Avoidance of withdrawal symptoms.

* Avoidance of overdose.

* Effective pain control.

* Treatment of psychological disorders such as anxiety.

* Acceptance of a suitable maintenance opioid regimen (Lewis & Williams 2005, Mehta & Langford 2006).

To achieve these aims an open and honest approach is required by both the patient and staff.

Literature review

A systematic review of the literature yielded just two relevant review articles and one case controlled retrospective review (Rapp et al 1995, Lewis & Williams 2005, Mehta & Langford 2006). Further information was obtained from textbooks on pain. Reference lists were attained from the evidence-based guidelines for the management of acute pain published by the Australian and New Zealand College of Anaesthetists (ANZCA 2005). This included one further review article focusing on acute pain in the opioid dependent patient (Mitra & Sinatra 2004). The British Pain Society's recommendations for the appropriate use of opioids for persistent non-cancer pain and the consensus document for consultation entitled Pain and Substance Misuse: Improving the Patient Experience were also referred to (British Pain Society 2004, Stannard 2006).

A case-controlled retrospective comparative study reviewed 202 patients with malignant and non-malignant pain, with opioid use of at least six months and significant postoperative pain (Rapp et al 1995). One hundred and eighty matched controlled pairs were included in the analysis. The main modality used for postoperative pain was Patient Controlled Analgesia (PCA). Total 24 hour usage of morphine was examined and a significant difference was found between the two groups. The results suggest that PCA use by the patient with prior opioid consumption can be expected to be significantly higher than in opioid-naive patients. The study showed different rates of tolerance to the side effects of opioids, increased tolerance to pruritis and nausea, but a higher incidence of sedation in the opioid tolerant group. The results showed higher pain scores in the opioid tolerant group. This could have been due to ineffective PCA parameters as the review does not offer information on these, or whether normal opioid use continued or a background was added to PCA.

The results suggest that morphine requirements are expected to be more than just replacement of the opioid. The authors also suggest that those patients with prior opioid use require longer postoperative analgesia.

Three review articles acknowledge the paucity of randomised controlled trials in the management of postoperative pain in opioid dependent patients, despite the increasing prevalence of opioid dependency (Mitra & Sinatra 2004, Lewis & Williams 2005, Mehta & Langford 2006). These reviews focused upon case reports, personal experience, expert opinion, and retrospective studies to guide the management of postoperative pain management in all opioid tolerant patients. The consensus from the reviews is that opioid tolerant patients will require larger doses of opioid postoperatively than opioid-naive patients and that preoperative opioid should be continued as a baseline and additional analgesia provided as required.

The first review proposes that the initial step to managing this complex problem is to recognise and assess these patients appropriately (Mitra & Sinatra 2004). This is required to formulate a peri- and postoperative management plan to provide adequate pain relief. The authors argue that it does not matter if the patient uses opioids legally or illegally as they both will exhibit diminished responses to postoperative doses of opioid. They recommend that for non-ambulatory surgeries, oral opioids are stopped after anaesthetic induction and converted to intravenous equivalents. PCA is the advised modality used either alone or in addition to epidural or regional techniques. This should be converted to account for the difference between oral dose and intravenous dose requirements: the intravenous dose is adjusted downwards from the oral dose because intravenous administration bypasses the gastrointestinal absorption variables, first pass hepatic clearance and metabolism. They recommend PCA with a background infusion to maintain the baseline opioid requirement, either by adding the equivalent to the patient's hourly oral dose requirement or the equivalent of one to two PCA boluses per hour. The size of the PCA bolus dose is not discussed. The authors suggest that an opioid patch could be continued instead of adding a background infusion to PCA to maintain baseline analgesia. For ambulatory surgery they recommend that the oral opioid should be supplemented with additional analgesia (20-50% increase above the baseline) to account for surgical pain. Lewis and Williams (2005) argue that both opioid patches and oral opioids should be stopped before surgery to avoid postoperative problems associated with delayed opioid absorption and inflexible dose delivery. Intra-spinal opioid pump systems should be continued to avoid upsetting a sensitive analgesic regimen. They advise that opioid tolerant patients require larger doses of postoperative opioids in order to prevent withdrawal symptoms. They suggest that although a baseline opioid requirement should be calculated from the preoperative opioid consumption, the actual requirements may be more or less than this depending upon the effect of the surgery. The surgery may change the nature of the pain or perhaps alleviate the pain. They claim that current evidence suggests only 50% of the preoperative dose is required to prevent withdrawal symptoms, however, this is not referenced. A variety of routes of administration are proposed depending on the nature of the surgery. To use PCA they advise to convert the oral 24 hour opioid dose to intravenous dose and to run between 50-100% of this calculated dose as a background infusion over 24 hours. The starting bolus dose of 1mg is recommended to be increased to at least 1.5mg-2.0mg for opioid tolerant patients.

Mehta and Langford (2006) recommend PCA with a higher bolus and shorter lockout time in opioid tolerant patients postoperatively. However, the addition of a background infusion to PCA is not discussed. They suggest that an opioid transdermal patch maybe left in situ with additional short acting analgesics for acute pain. In terms of buprenophine patches they advise leaving the patch and adding immediate release buprenophine to avoid the risk of agonist-partial agonist interaction. Current pain textbooks recommend the use of PCA with a background infusion and larger bolus dose for opioid dependent patients to manage postoperative pain (Macintyre & Ready 2001, ANZCA 2005). The British Pain Society advises that PCA can be used for acute pain management for patients with a history of substance abuse and advise that a background infusion is required as well as an increased bolus dose (Stannard 2006). The literature comments that epidural alone, even if it contains opioid, will not prevent opioid withdrawal symptoms (Mitra & Sinatra 2004, Stannard 2006).

All of the reviews advocate the use of multimodal analgesia, for example, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), ketamine and regional anaesthesia, in addition to opioids where possible, to improve pain and to opioid spare (Mitra & Sinatra 2004, Lewis & Williams 2005, Mehta & Langford 2006). There is a wealth of research to support the use of multimodal analgesia for opioid sparing properties (Perttunen et al 1999, Remy et al 2005).


Data collection was achieved through the development of a questionnaire by the author based on the findings of the literature. This was emailed to pain nurses in 23 hospital-based pain services in London. A full explanation of the purpose of the enquiry was given and participation in completing the questionnaire was voluntary. The pain nurses had two weeks to complete and return the questionnaire to the author.

It was confirmed that ethical approval was not required, as data collection was for audit purposes.

The questionnaire covered the following areas:

* Protocols for managing postoperative pain in cancer patients with opioid tolerance.

* Protocols for managing other opioid dependent patients.

* Regular practice used to guide the management of opioid tolerant patients.

* PCA use for opioid tolerant patients.

* Conversion of regular opioids to other forms of opioids.

* Other methods used to manage opioid dependent patients.

Most questions required a 'yes/no' answer. One question was open ended.


Ten hospitals returned the questionnaire, six of which were acute pain services and four hospitals with combined acute and chronic services. The questionnaires were analysed by the author and nurse consultant. The data are presented as frequencies.


Only one hospital has a protocol for opioid tolerant patients and this is not specific to postoperative pain. Although nine of the hospitals state that they have a regular practice in dealing with opioid tolerant patients with postoperative pain, this was not evident in their answers.

Nine hospitals stated that they have a formalised practice but they appear to assess patients individually. This could be argued to be an appropriate method of managing these patients but it could be difficult to achieve in practice. Good communication systems need to be established to facilitate assessing patients preoperatively to formulate postoperative plans. There are patients who are not admitted electively and those who are operated on out of hours who may be missed. A protocol during these times would provide some guidance for those healthcare professionals who do not have experience in managing opioid dependent patients and calculating opioids. One hospital commented that it is initiating a practise where long term opioid dependent patients are made known to the pain team when they are admitted into hospital. They do not comment on how this is achieved or how effective it is in practice. This issue needs to be addressed and requires the pain service to communicate with pre-assessment clinics and anaesthetists so that these patients can be identified. Unless this important initial identification is made it is difficult to plan for appropriate postoperative pain management, even if a protocol exists.

The majority of the hospitals were consistent with the literature and continued the patient's preoperative opioid requirements with additional analgesia as appropriate. There is little consensus between the hospitals as to how this is achieved or even between patients in the same hospital. When using PCA, all of the hospitals stated that they used different methods for converting different types of opioids to PCA. Only seven hospitals responded that they used a particular formula to convert the preoperative opioid to PCA.

The majority of the literature recommends omitting the preoperative opioid and substituting it with another regimen, mainly PCA. This is due to potential changes in opioid requirements depending upon the effect of the surgery (Lewis & Williams 2005). However, nine of the hospitals stated that they kept the regular opioid going while the patient was on PCA. The majority of the literature advises to stop the oral opioid and to use a background infusion with PCA and a higher bolus dose (Macintyre & Ready 2001, Mitra & Sinatra 2004, ANZCA 2005, Lewis & Williams 2005, Stannard 2006) but, only two hospitals routinely use a background infusion in addition to PCA. An additional four hospitals replied that they may use a background infusion. Only half of the hospitals replied that they would increase the size of the PCA bolus despite the literature advising that a larger bolus dose would normally be required in opioid tolerant patients. Some of the hospitals commented that an opioid patch may be left on for opioid maintenance and this is supported in the literature (Mehta & Langford 2006).

Local practice consists of formal guidelines for the postoperative management of opioid tolerant patients and is included in the author's trust's PCA policy. This is based upon the work of Lewis and Williams (2005). Preoperative opioids are stopped postoperatively. The total daily opioid intake is calculated and converted to the equivalent morphine intravenous dose. Fifty percent of the total opioid daily dose is given as a background infusion over 24 hours via PCA. The starting PCA bolus dose is increased to at least 1.5-2mg depending on the individual patient status and preoperative requirement. The background infusion is 50% of the opioid dose to allow for both increases and decreases in postoperative requirements. This may not be a perfect formula, but it is a consistent formula which can be titrated up or down depending on the individual's requirement. A PCA machine that allows for individual settings is required to allow this to happen in practise. The intravenous route used for PCA allows for 100% bioavailability and a rapid onset of analgesia. This is especially important in the initial postoperative period when oral administration of opioids may have unpredictable results due to impaired absorption in the stomach (Bennett & Brown 2003). Opioid patches may also have unpredictable absorption rates in the postoperative period due to pharmacokinetics which change in the presence of oedema and fever (Fallon 2003).

Once the patient is able to resume an oral analgesic regimen, the PCA opioid dose can be converted back to equianalgesic oral dose. This will be individualised to reflect the individual patient's requirements (Lewis & Williams 2005). A suggested PCA regimen for a patient who presents for surgery on oral long acting morphine sulphate (100mg MST twice daily) plus oramorph 30mg four times a day (see Table 11).

A suggested PCA regimen for a patient on oxynorm 20 mg every 4 hours who presents for surgery (see Table 12).

One hospital stated that medicines for neuropathic pain are difficult to convert to IV equivalents and that this can be challenging. The literature advocates that ketamine can be used as an adjunct to opioids in opioid tolerant patients to improve pain relief, to prevent and improve neuropathic pain, reduce opioid requirements and reduce opioid side effects (Bell et al 2003, Mitra & Sinatra 2004, Mehta & Langford 2006, Visser & Schug 2006). Ketamine is a NMDA receptor antagonist and there is evidence to suggest that NMDA receptors are involved in many types of pain including postoperative pain and neuropathic pain. Ketamine can be given intravenously as a low dose infusion for those unable to tolerate oral regimens and acts as an antagonist at the NMDA receptors. The results of the questionnaire are interesting: the reason for this lack of consensus between the hospitals is probably a reflection of the limited evidence available to guide practice. In addition to this, the majority of hospitals that responded dealt mainly with acute pain and this may have influenced their management of patients who present with opioid tolerance. It could be argued that combined acute and chronic pain teams may have more experience in caring for patients with opioid tolerance and are able to transfer these skills across to the acute setting.


The evidence available for the management of postoperative pain in opioid tolerant patients is limited. The results of the questionnaire are consistent with the literature in that preoperative opioid is usually maintained with additional analgesia. However, the results show that there is little consensus between the hospitals and between different patients in how to achieve this.

Whichever method is used the aim should be to provide good pain relief, avoid withdrawal and prevent side effects, ensuring that a sufficient dose reaches the site of action, with adequate absorption and distribution (Kongsgaard cited in Breivik et al 2003). More studies in this area are required as the number of patients dependent on opioids is increasing (Mehta & Langford 2006). Further studies could also enable bodies like The British Pain Society to develop protocols and recommendations for the postoperative management of patients with opioid tolerance and other opioid tolerant groups.

Five key points for caring for patients with opioid tolerance:

* Good communication: preoperative assessment by recovery staff/preassessment. Identification of patients who are at risk. Good communication between pre-assessment staff/recovery staff and anaesthetist/pain service.

* Formulisation of peri and postoperative plan.

* Use of adjuvant drugs and regional analgesia--peri and postoperatively to 'opioid spare'.

* Physical dependence requires baseline preoperative opioids to be maintained to prevent withdrawal symptoms.

* Postoperative opioid requirements may vary depending on the effects of surgery.


Australian and New Zealand College of Anesthetists (ANZCA) 2005 Acute Pain management: Scientific Evidence (2nd Edn) Australian and New Zealand College of Anesthetists and Faculty of Pain medicine

Bell R, Eccleston C, Kalso E 2003 Ketamine as adjuvant to opioids for cancer pain. A qualitative systematic review Journal of Pain and Symptom Management 26 (3) 867-874

Bennett PN, Brown MJ 2003 Clinical Pharmacology (9th Edn) London, Churchill Livingstone

Collett B-J 1998 Opioid tolerance: the clinical perspective British Journal of Anaesthesia 81 (1) 58-68

Doverty M, Somogyi A, White J et al 20001 Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine Pain 93 155-163

Fallon M 2003 Opioid switching and rotation In: Sykes N, Fallon M, Patt, R (Eds) Clinical pain management: Cancer Pain London, Arnold

Higginson I, Hearn J, Addington-Hall J 2003 Epidemiology of cancer pain In: Sykes N, Fallon M, Patt R (Eds) Clinical pain management: Cancer Pain London, Arnold

Kongsgaard U 2003 Clinical Trials: Cancer pain In: Breivik H, Campbell W, Eccleston C (Eds) Clinical Pain Management: Practical Applications & Procedures London, Arnold

Lewis N, Williams J 2005 Acute pain management in patients receiving opioids for chronic and cancer pain Continuing Education in Anaesthesia Critical Care and Pain 5 (4) 127-129

Macintyre PE, Ready LE 2001 Acute Pain Management: A Practical Guide (2nd Edn) London, Saunders Publications

Mehta V, Langford RM 2006 Acute pain management for opioid dependent patients Anaesthesia 61 (3) 269-276

Mitra S, Sinatra R 2004 Perioperative management of acute pain in the opioid-dependent patient Anesthesiology 101 (1) 212-227

Perttunen K, Nilsson E, Kalso E 1999 I.V. diclofenac and Ketorolac for pain after thoracoscopic surgery British Journal of Anaesthesia 82 (2) 221-227

Rapp S, Ready B, Nessly M 1995 Acute pain management in patients with prior opioid consumption: a case controlled retrospective review Pain 61 195-201

Remy C, Marret E, Bonnet F 2005 Effects of acetaminophen on morphine side effects and consumption after major surgery: Meta-analysis of randomised controlled trials British Journal of Anaesthesia 94 (4) 505-513

Stannard C (Ed) 2006 Pain and substance abuse: improving the patient experience A Consensus document for consultation 2006 London, The British Pain Society

The British Pain Society 2004 Recommendations for the appropriate use of opioids for persistent non-cancer pain: a consensus statement London, The British Pain Society

Twycross R 2003 Cancer pain syndromes In: Sykes N, Fallon M, Patt R (Eds) Clinical pain management: Cancer Pain London, Arnold

Visser E, Schug SA 2006 The role of ketamine in pain management Biomedicine & Pharmacotherapy 60 341-348

About the author

Nicola Bourne

BA(Hons), RN, MSc Pain


Clinical Nurse Specialist,

Pain Management,

Imperial College

Healthcare NHS Trust

by Nicola Bourne Correspondence address: Pain Clinic, St Mary's Hospital, Praed Street, London, W2 1NY. Email:
Table 1 Symptoms and signs of opioid withdrawal

* Restlessness

* Muscle aches/pains

* Insomnia

* Dysphoria

* Irritability

* Lacrimation

* Sweating

* Piloerection (gooseflesh)

* Yawning

* Diarrhoea

* Nausea and Vomiting

* Tachycardia

* Abdominal cramps

* Fevers/chills

* Anxiety

* Rhinorrhoea

* Dilated pupils

* Hypertension

Table 2 Possible indicators of addiction

* Polysubstance use

* 'Doctor shopping', including
forging, losing and selling

* Manipulatory behaviour

* Escalation of use

* Injection of oral preparations

* Seeking drugs from non-medical

* Selling of drugs

* Inability to function socially or in

Table 3 Literature review results for managing opioid dependent

                                                  Continue baseline
Authors                      Pre-op agreed plan       analgesia

Mitra & Sinatra 2004              [check]
  (non-ambulatory surgery)
Mitra & Sinatra 2004              [check]              [check]
  (ambulatory surgery)
Lewis and Williams (2005)         [check]              [check]
Mehta & Langford (2006)           [check]              [check]

                             Substitute baseline
                             with background       Bolus dose
Authors                      PCA infusion          adjustment

Mitra & Sinatra 2004                               Not given
  (non-ambulatory surgery)
Mitra & Sinatra 2004                               +20-50%
  (ambulatory surgery)                             additional
Lewis and Williams (2005)    [check] 350-100%      1.5-2mg
                               of daily dose
Mehta & Langford (2006)      Not discussed         Larger bolus dose
                                                     with shorter
                                                     lockout time

Table 4 Speciality of the hospitals (n=10)

Speciality                Frequency

Acute pain                    6
Acute and chronic pain        4

Table 5 Protocols for the management of postoperative
pain in opioid tolerant patients (n=10)

                              Yes    No

Protocol for opioid            0     10
dependent cancer patients?

Protocol for opioid            1      9
dependent patients?

Table 6 Regular practice for opioid tolerant patients with
postoperative pain (n=10)

                              Yes    No

Regular practice for opioid    9      1
dependent patients?

Table 7 Is the same method used for PCA for patients who
are on all forms of opioid preoperatively? (n=10)

                              Yes    No

The same method for used?      0     10

Table 8 PCA settings (n=10)

                                                Yes   No

Do you stop the regular opioid while on PCA?     1     9
Do you use a larger bolus on the PCA?            5     5
Do you add a background infusion to the PCA?     2     8
Do use a specific formula to convert opioids?    7     3

Table 9 If you don't use PCA for this group of patients,
how do you manage their postoperative pain? (n=10)

Epidural                                  5
Additional prn opioid to regular opioid   2
No answer                                 3

Table 10 If you continue the patient's regular opioids, do
you increase their regular and prn doses? (n=9)

                                  Yes   No

Increase regular and prn doses     7     2

Table 11 Clinical example of PCA regimen

* Preoperatively the basal opioid
requirement is calculated = 320
oral morphine/day (200mg MST +
120mg oramorph).

* Converted from oral to iv
morphine (ratio 2:1) = 160mg iv

* Divide by 2 to give 50% of daily
morphine intake = 80mg/day.

* Divide by 24 to give hourly dose =

* Therefore appropriate background
infusion rate = 3mg/hr morphine.

* Appropriate bolus dose between
2-3 mg morphine. Lockout five

Table 12 Clinical example of PCA regimen

* Preoperatively the basal opioid requirement is calculated = 120
oral oxynorm (20mg X 6)

* Converted from oral to iv morphine (ratio 1:1) = 120mg iv

* Divide by 2 to give 50% of daily morphine intake = 60 mg iv

* Divide by 24 to give hourly dose =2.5mg/hr

* Therefore appropriate background infusion rate = 2.5mg/hr morphine

* Appropriate bolus dose between 1.5-2.5 mg morphine. Lockout five
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