Prescribing drugs of dependence in general practice

Part C2 - The role of opioids in pain management - Chapter 6

Overview of opioid analgesics

Download PDF

Last revised: 02 Jun 2020

There are significant difficulties translating evidence from clinical pain trials into pain management in practice. This is not only because of issues around the number, quality, bias, duration and construction of studies,90,96,286 but also because pain is a subjective experience influenced by a complex range of factors.

Additionally, labels such as CNCP do not just describe one condition, but a variety of conditions with diverse aetiologies, for which the evidence for therapeutic impact varies. Patients with the same condition will have unique pain experiences and respond differently to therapeutic interventions.

No analgesic drug works well in all patients. Most analgesics work well in a small proportion of patients. There is often a strong placebo (contextual) effect. Pain relief from therapeutic interventions is not normally distributed but is usually bimodal, being either very good (above 50%) or poor (below 15%).287–289 Hence, using averages is unhelpful and misleading because few (if any) patients experience ‘average’ pain relief and it tells us nothing about how many patients will experience clinically useful analgesia.221

Clinical trials designed for regulatory purposes consider single interventions and fixed dose regimens, which may exacerbate adverse events and withdrawals, resulting in higher failure rates.221 For example:

  • failure rates for NSAIDs are ≥70% in osteoarthritis, ≥80% in chronic low back pain and 58–72% in ankylosing spondylitis221
  • for neuropathic conditions, antidepressants and anticonvulsants have failure rates of ≥70% in painful diabetic neuropathy and post-herpetic neuralgia, and ≥87% in fibromyalgia.221

This does not reflect the clinical reality of choosing options and individualising doses. For example, about half of osteoarthritis patients with moderate or severe pain on treatment had a significant (30%) reduction in pain intensity when switched to another NSAID.290

On review of pain trial studies, it was noted that patient response distributions are U-shaped, not Gaussian, making average values inappropriate. In fact, the ‘average pain score’ data may mislead. Since 2011, the editors of the Cochrane Pain, Palliative and Supportive Care Systematic Review Group have established new criteria for examining evidence in pain.291 It is now standard to measure ‘responder’ analyses; reporting the proportion of patients achieving outcomes that patients consider worthwhile221 (that is, the proportion of patients who experience at least 30–50% pain reduction).

A minority of patients achieve very large reductions in pain (responders) whereas the majority achieve little relief (non-responders).292 Individual patient analyses for chronic pain interventions have shown that people who respond also experience improvements in fatigue, depression, and sleep interference.53,293

It is standard for patients to delegate ‘at least 50% pain reduction’ as a successful outcome. It is the minimum outcome that patients want,293 and may be associated with restoration of function, work, and quality of life lost with chronic pain.29 Clinically, this has major implications for practice. Use of responder analysis changes judgement of benefit and risk and suggests that classical trials in pain using ‘averages’ may underestimate efficacy.221

Responder analysis also supports clinical practice focus on individual responses to therapy. It enables trialling numerous treatment options to achieve pain relief for the individual.221 Similarly, non-responders should stop treatment that does not work.

The evidence of failure for paracetamol295 and NSAIDs296,297 in musculoskeletal pain and the poor efficacy for opioids, anticonvulsants (gabapentin, pregabalin) and antidepressants for neuropathic pains100 need to be reconsidered in the light of responders and non-responders. Evidence about a single intervention needs to be considered with individual patient circumstances, tempered with wisdom and experience to be used sensibly in clinical setting.286

It is with these caveats in mind that evidence of effect of pain medications in chronic pain should be considered.

The efficacy of opioid therapy in acute pain is supported by strong evidence from RCTs5,7 and by systematic reviews in cancer pain,298,299 palliative care300 and opioid dependence.301

CNCP is very different. It is not a diagnosis, but a group of entities with various aetiologies. The pathophysiologic descriptors of these aetiologies are still changing. Studies examining chronic pain often have methodological weaknesses that make interpretation difficult, and transfer into clinical practice requires care.

The evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited; however, this does not mean there is no evidence to guide care.

Evidence in different chronic pain conditions

Musculoskeletal pain

Musculoskeletal conditions account for a large proportion of general practice opioid prescriptions.302 In trials with at least 12 weeks’ duration of opioids for managing osteoarthritis, there is:

  • fair evidence for tramadol303
  • limited evidence for transdermal buprenorphine303 – it has been shown to be effective and well tolerated (with analgesic effects similar to tramadol)304
  • limited evidence for tapentadol for arthritic pain.303,305

Reviews of opioid therapy in chronic low back pain provide some support for short-term use, but evidence beyond three months is lacking.306,307 In trials with at least 12 weeks’ duration of opioids for managing chronic low back pain, there is some evidence for transdermal buprenorphine,308 tapentadol305 and tramadol/paracetamol combinations.309–311

Caution should be used in extrapolating evidence from short-term trials into longer-term care. Analysis of openlabel extension trials provides some support for sustained opioid effect, but in only 25% of patients originally enrolled.312 The harms (abuse of prescribed opioids, mortality) of long-term opioid therapy in clinical practice are underestimated by long-term extension studies, probably because patients with major medical diseases and mental disorders were excluded.312

Neuropathic pain

Several guidelines support opioid use in neuropathic pain, but not as a first-line treatment. When first-line medications fail or provide inadequate pain relief, tramadol or a conventional opioid analgesic may be useful as a second-line or third-line treatment.94,96 For management of neuropathic pain:

  • tramadol has weak GRADE recommendations for its use; generally it is considered a second-line treatment  because of safety and tolerability.96 The tramadol NNT for 50% pain reduction is approximately five96
  • strong opioids, particularly oxycodone and morphine, have weak GRADE recommendations for use and are recommended as third-line treatments mainly because of safety concerns.96 The oxycodone NNT for 50% pain reduction is approximately four.96 Other reviews are less favourable for oxycodone and report a moderate benefit (at least 30% pain relief) NNT at 5.7.313

The NNT for benefit in opioids appears similar to other drugs (eg antidepressants, anticonvulsants) used in painful neuropathies such as diabetic neuropathy, post-herpetic neuralgia, peripheral nerve injury, HIV neuropathy, central pain, trigeminal neuralgia and mixed neuropathic pain. The NNT for these non-opioid medications range from around four to eight. Continual critical appraisal of all classes of medication used in long-term pain management is warranted.

Combination therapies are common though few are studied. One meta-analysis demonstrated modest superiority of gabapentin plus opioid versus gabapentin alone, although the combination produced significantly more dropouts due to accentuated side effects related to combination treatments.314


There is limited evidence for opioids for management of CNCP and insufficient evidence to determine long-term benefits. For well-selected patients with no history of SUDs, proper management with opioids can contribute to long-term pain relief.11However, long-term opioid treatment (≥26 weeks) benefits only about 25%

Presented in alphabetical order


Buprenorphine is a partial agonist at mu opioid receptors and an antagonist at delta and kappa receptors. It is typically used for analgesia (in low-dose patch formulation) and in ORT, where sublingual formulations are usually used.

Musculoskeletal pain

There is limited evidence regarding buprenorphine for CNCP due to a lack of high-quality RCTs.303 However, transdermal buprenorphine for osteoarthritis has been shown to be effective and well tolerated, with analgesic effects similar to tramadol.304

Neuropathic pain

Case reports suggest that buprenorphine is effective in peripheral315,316 and central neuropathic pain in the clinical setting.317 However, large trials are lacking and currently there is not enough evidence to support or dispute efficacy of buprenorphine in any neuropathic pain condition.318

Addiction medicine

Buprenorphine is listed for use in ORT (as Section100 [S100]).

In practice

Buprenorphine is PBS listed for chronic severe pain and ORT.

Transdermal patches (used for pain, not ORT) generally provide a week of analgesia. Occasionally, patients complain that there is release of the drug from the transdermal patch for only six, or rarely five, days. In these instances, the patches may need to be changed more frequently than weekly.

Buprenorphine can be safely used in patients with renal impairment and has less immunosuppressive effect than pure mu-opioid agonists.319

As long as sedative medication is not given concurrently, the risk of respiratory depression with buprenorphine is low compared to morphine, methadone, hydromorphone and fentanyl.320 There is a ceiling effect for respiratory depression but not for analgesia.321 If buprenorphine-induced respiratory depression occurs it may be completely reversed with naloxone,319 although higher than usual doses and a longer duration infusion of naloxone are required.322

Withdrawal symptoms may occur if buprenorphine is ceased after long-term treatment; however, these symptoms are milder and more delayed in onset (≥72 hours) compared with other opioids.320

Buprenorphine binds strongly to the mu receptor site, but does not fully activate it.323 Therefore, if buprenorphine is combined with pure mu agonists (eg morphine, fentanyl), interactions may occur. For example, if a pure mu agonist is given to a person on maintenance buprenorphine it may be less effective. Conversely, buprenorphine could theoretically cause a withdrawal reaction if given to a patient taking longer-term opioid (mu) therapy.323

Antagonism of response to pure mu agonists (precipitated withdrawal) can occur with buprenorphine but it has only been demonstrated at buprenorphine doses exceeding the ranges used for analgesia (eg at dosages for ORT). In practice, these drug interactions are unlikely.


Codeine is a weak mu receptor agonist (200-fold weaker affinity than morphine) and its analgesic action depends on the metabolism of about 10% of the dose to morphine, via CYP2D6.324,325 Ultrarapid metabolisers have significantly higher levels of morphine and morphine metabolites after the same dose of codeine.326 Poor metabolisers do not produce any morphine or gain any analgesic effect.

Codeine is subject to misuse and dependence, and is the commonest prescription opioid associated with fatal overdoses in Victoria.327 Rates of misuse average between 21% and 29%, and dependence average between 8% and 12%.327

Musculoskeletal pain

Codeine is commonly used in combination with other minor analgesics (eg paracetamol, ibuprofen). There is highquality evidence that combination codeine medicines provide clinically important pain relief in the immediate term, but this is mostly in acute pain.16

In practice

Codeine is classified as a weak opioid. It is listed by the PBS for mild to moderate pain. There is no role for codeine in chronic pain.

A single 60 mg dose provides good analgesia to few adults: 12 patients need to be treated for one to achieve a 50% reduction in postoperative pain.328 OTC preparations containing low doses of 8–15 mg codeine phosphate are considered sub-therapeutic.

Combining codeine with non-opioid analgesics provides limited additional analgesic benefit: seven patients need to be treated with ibuprofen 400 mg/codeine 25.6–60 mg for one to obtain at least a 50% reduction in postoperative pain when compared to treatment with ibuprofen 400 mg alone.328,329

Given the variability in response and risk of harm, use of codeine should be closely monitored.


In November 2011, the TGA decided to remove the registration of dextropropoxyphene in Australia.330 It was withdrawn from the Food and Drug Administration (FDA) in the US due to risks of QT-interval prolongation and possibility of Torsades de Pointes (TdP) and cardiogenic death.

Oral dextropropoxyphene alone is a poorly effective analgesic.331 In combination with paracetamol, it also provides little benefit above paracetamol alone.332

In practice

Dextropropoxyphene has now been limited to authorised users for previous users only. To prescribe this medication, GPs need to:

  • be aware that the medicine is only approved for use in patients not able to be adequately treated with other mild pain killers
  • have considered the contraindications for the medicine outlined in the product information and have explained them to the patient at the time of prescribing
  • have considered any recent changes to the patient’s clinical presentation or biochemical status
  • have warned the patient at the time of prescribing about appropriate use of the medicine
  • be satisfied at the time of prescribing that the patient’s history does not indicate that the patient is at risk of accidental or intentional self-harm.

The conditions also require that a signed Prescriber Confirmation form is presented to the pharmacist dispensing these medicines before supplying them to the patient every time a patient presents for a prescription.


Fentanyl is a highly potent opioid, which is active at the mu receptor. It is metabolised almost exclusively in the liver to minimally active metabolites. This makes it particularly useful in renal failure: <10% of unmetabolised fentanyl is renally excreted.333

It is available as transdermal patches, oral transmucosal lozenges or lollipops and injectable preparations. The transdermal system offers an excellent option for long-term treatment of cancer pain, but the RACGP believes it is not suitable for CNCP. A 25 ug/hour fentanyl patch is equivalent to approximately 90 mg of oral morphine per day. Oral transmucosal fentanyl rapidly achieves high plasma concentrations and is indicated to treat breakthrough pain in cancer patients who are not opioid naïve.333

Fentanyl-related mortality is currently relatively low in Australia compared to the US and parts of Europe. However, fentanyl misuse is on the rise in Australia with a large proportion of these deaths occurring among at-risk groups who inject drugs.334 Because of the misuse potential, this drug should be used only as indicated. It has known diversional potential, extremely high street value and risk of misuse.

In practice

Fentanyl is PBS listed for severe disabling pain and is usually used in cancer care or in acute hospital settings.

In the opioid-naïve patient, there is a significant risk of toxicity and overdose. Fentanyl patches are not suitable to be used as the initial agent in the management of pain for opioid-naïve patients due to high morphine-equivalent doses. Fentanyl should only be used in the case of cancer pain when all other options have been exhausted.

Be aware that local heat (eg hydrotherapy pool) may increase absorption from the patch.


Hydromorphone is an effective strong opioid acting as a mu receptor agonist. It is approximately five times as potent as morphine and provides slightly better clinical analgesia than morphine, but has similar adverse effects.335,336 The main metabolite of hydromorphone is hydromorphone-3-glucuronide (H3G), which is dependent on the kidneys for excretion, has no analgesic action and can lead to dose-dependent neurotoxic effects.337

It is available as solution for injection, oral liquid and tablets. It also has extremely high potential for misuse and high street value for those who divert this drug.

In practice

Hydromorphone is PBS listed for severe disabling pain, but in practice is usually restricted to malignant pain, or patients undergoing dialysis. It is not suitable to be used as the initial agent in the management of pain for opioidnaïve patients.


Methadone is a synthetic opioid acting as an agonist at the mu receptor with additional ketamine-like antagonism at the N-methyl-D-aspartate receptor. It is commonly used for the maintenance treatment of patients with an addiction to opioids and in patients with chronic pain.

It has good oral bioavailability (70–80%), high potency, a long duration of action and no active metabolites.338 But it also has a long and unpredictable half-life (mean of 22 hours; range 4–190 hours), which increases the risk of accumulation.339

Concurrent administration of other drugs that are metabolised by the P450 enzyme system may have significant effects. P450 inducers (eg carbamazepine, rifampicin, phenytoin, St John’s wort (Hypericum perforatum), some antiretroviral agents) may increase methadone metabolism, which lowers methadone blood levels and leads to potential reduced efficacy or even withdrawal.340 Use of P450 inhibitors (eg other antiretroviral agents, some SSRIs, grapefruit juice, antifungal agents) may lead to raised methadone levels, which increases risk of adverse effects or overdose.340 Checking for drug interactions with methadone can be done online.

In practice

Methadone is PBS listed for severe disabling pain and for ORT (as S100). Two formulations are available in Australia. Methadone liquid is used once daily for maintenance in opioid dependent patients. Methadone tablets may be used two to four times daily to manage persistent pain.341

Methadone use is usually confined to specialist pain medicine areas342 as it has complicated and unpredictable pharmacokinetics. Extreme caution must be taken when inducting a person onto an appropriate dose of methadone, with a slow titration regimen and close monitoring required. It may take up to two weeks to reach steady state levels, and drug accumulation may cause excessive sedation and high risk of overdose and death if the dose is increased rapidly.341


Morphine has been the most widely used opioid in acute, persistent and cancer pain, and remains the standard against which other opioids are compared.

The main metabolites of morphine (primarily formed by hepatic glucuronidation) are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G is a mu opioid receptor agonist and is the main mediator of analgesia.343 M3G has very low affinity for opioid receptors and no analgesic activity, but may be responsible for the neurotoxic symptoms such as hyperalgesia, allodynia and myoclonus, sometimes associated with high doses of morphine.325 Both metabolites are renally eliminated.

Higher doses, older age, impaired renal function and the oral administration (due to first-pass metabolism) are associated with higher M3G and M6G concentrations and therefore with the potential risk of severe long-lasting sedation and respiratory depression.344,345

While the clinical significance is uncertain, morphine is the most immunosuppressive of the currently available opioids.346,347

There has been a decrease in morphine prescribing in Australia.334 Prescriptions are most prevalent among older Australians.

Musculoskeletal pain

The evidence for morphine in managing CNCP, including low back pain, is poor.303

Neuropathic pain

Strong opioids including morphine have weak GRADE recommendations for use and are recommended as third line mainly because of safety concerns.96

In practice

Morphine formulations are indicated by the PBS for severe disabling pain (cancer, palliative care) and chronic severe pain. Commencement doses vary according to patient selection and age.


Oxycodone action appears to be mediated primarily by mu receptor agonism. Oxycodone contributes the majority of drug effect, as its metabolites, noroxycodone and oxymorphone (via CYP3A4), are only weakly active. However, oxycodone concentration may be dependent on CYP2D6 activity, resulting in ultrarapid metabolisers experiencing better analgesic effects than poor metabolisers, but also higher toxicity.348,349

Paradoxically, in acute postoperative pain, the CYP2D6 genotype does not appear to influence oxycodone requirements.350 There is an increasing use of oxycodone in the acute, hospital and perioperative settings as it has a faster onset of action than morphine, better oral bioavailability, longer duration of action, fewer concerns about metabolites and lower rate of adverse effects based on these pharmacological properties.350–352

Oxycodone-related deaths are currently relatively low in Australia; they are not comparable to numbers reported in the US.334

Musculoskeletal pain

The evidence for oxycodone in the management of CNCP is poor.303

Neuropathic pain

Strong opioids including oxycodone have weak GRADE recommendations for use and are recommended as third line mainly because of safety concerns.96

In practice

Oxycodone is PBS listed for severe disabling pain and chronic severe pain. It is particularly popular in hospital and acute pain settings. Care should be used in rehabilitation settings to minimise chronic use.

Care should also be taken by GPs continuing to prescribe oxycodone in the community post discharge from the hospital setting. All patients should have plans to be weaned off their opioid analgesics post discharge.

The use of oxycodone is increasing rapidly and addiction specialists report that it is often a drug of choice for misuse. A combination of oxycodone with naloxone has recently been released in Australia. This combination substantially reduces the chance of constipation,353 but the risks of misuse and diversion still exist.

Note that St John’s wort (H. perforatum) induces metabolism of oxycodone, significantly reducing its plasma concentrations and efficacy.354


Pethidine is a synthetic opioid active at the mu receptor. IM pethidine has been widely used in Australia for a range of pain problems. Its use is decreasing because of multiple disadvantages compared to other opioids. Repeated dosing or renal failure leads to accumulation of its active metabolite (norpethidine), which is associated with neuroexcitatory effects that range from nervousness to tremors, twitches, multifocal myoclonus and seizures.355

When used parenterally, pethidine does not provide better analgesia than morphine, but does induce more nausea and vomiting than morphine.356

In practice

Use of pethidine is discouraged in favour of other opioids.357,358

It has high addiction potential and is not recommended for the treatment of persistent pain.

Pethidine is no longer indicated for the treatment of migraines.


Tapentadol is a combined weak mu agonist and noradrenaline reuptake inhibitor (acting on descending pain inhibition pathways) with no active metabolites.359–361 In a number of chronic pain conditions, tapentadol shows efficacy that is comparable or better than conventional opioids but with reduced rates of gastrointestinal adverse effects (eg nausea, vomiting, constipation), which results in less treatment discontinuation.362

At doses up to the maximum recommended 500 mg/day, tapentadol has no effect on heart rate or blood pressure due to noradrenaline reuptake inhibition, even in patients with hypertension and/or on antihypertensives.363 However, as it is metabolised by the liver, impaired hepatic function may require dose adjustment.364

Despite widespread use over several years in the US and Europe, there are only two reported cases of an overdose death.365 Although it is a controlled medicine in all countries, tapentadol shows a lower rate of misuse and diversion than oxycodone and hydrocodone and a rate comparable to tramadol.366,367 There are limited data to support a role for tapentadol in cancer pain.368

Musculoskeletal pain

Currently, relatively few RCTs have studied tapentadol. There is evidence of benefit in osteoarthritis, low back pain and postoperative pain.305,369–371 Three randomised trials studying tapentadol for managing chronic pain of osteoarthritis and low back found that 32% of patients received greater than 50% pain relief.303

Neuropathic pain

Due to effect of noradrenaline uptake inhibition on descending pathways of pain, tapentadol modulates increased conditioned pain seen with neuropathic pain.372 This effect has been confirmed in diabetic neuropathy.360

In practice

Tapentadol is PBS listed for chronic severe pain.

Start at low dose 50 mg and titrate the dose according to response increase: every three days, increase the dose by 50 mg for each twice-daily dose until adequate analgesia or the 50 mg OME dose of 125 mg/day is reached.


Tramadol acts as both a weak opioid agonist and as a serotonin and noradrenaline reuptake inhibitor. Due to the combined effects, it is commonly referred to as an atypical centrally acting analgesic.361,373

Tramadol is metabolised by CYP2D6 to an active metabolite, O-desmethyltramadol (M1), which is a more potent mu opioid receptor agonist than the parent drug.374 Hence, patients who are poor metabolisers receive less analgesic effect from tramadol.375

The adverse-effect profile of tramadol is different from other opioids. The most common side effects are nausea and vomiting, which occur at rates similar to morphine.376,377 However, tramadol has less effect on gastrointestinal motor function than morphine.377,378 It causes less respiratory depression than other opioids at equianalgesic doses.379,380 Tramadol does not increase the incidence of seizures compared with other analgesic agents,381,382 although there is a risk of inducing serotonin toxicity when tramadol is combined with other serotonergic medicines, in particular SSRIs.383

Tramadol has a lower potential for misuse than conventional opioids.384

Musculoskeletal pain

There is fair evidence for tramadol in managing osteoarthritis.303

Neuropathic pain

Tramadol has a weak GRADE recommendation for use in neuropathic pain,96 and is regarded as generally second line because due to tolerability and safety.96,385

In practice

Tramadol is listed on the PBS for acute or chronic pain not responding to aspirin and/or paracetamol; short-term treatment of acute pain.

Side effects often limit use, but tramadol can be useful if tolerated.


The practical usefulness of opioids is related to the available formulations (Table 10).

Approximate equivalence doses

Oral morphine is the standard that other opioids are measured against. Full opioid agonists given in equianalgesic doses produce the same analgesic effect.387 However, accurate determination of equianalgesic doses is difficult due to individual variability in pharmacokinetics and dynamics.147

There are several published tables providing approximate equianalgesic doses. These are typically based on singledose studies in opioid-naïve subjects and may not be as relevant when conversions are made after repeated doses of an opioid.337 They also do not take into account incomplete cross-tolerance and patient-specific factors.342 

Converting to methadone requires special caution. Regardless of how much other opioid the patient is being prescribed, commence methadone at low doses in accordance with the National guidelines for medicationassisted treatment for opioid dependence  or in consultation with pain or addiction specialists.

Box 13.

Useful tools for calculating equivalent doses

Commencing and increasing dosage

Starting doses are a guide only and may vary according to the clinical situation, condition of the patient and previous analgesic requirements. For example, older patients generally require lower opioid doses.388

At each review, assess pain intensity, cardiorespiratory status, level of sedation and other adverse effects. Titrate dose according to response, sedation score (an early indicator of respiratory depression) and respiratory rate. Use small dose increments as the dose required may vary more than 10-fold between patients of similar age, irrespective of weight.388

Adjust the dose of controlled-release (CR) opioids, not the frequency of administration. However, if increasing the dose fails, it may occasionally be appropriate to administer doses more frequently for patients with pain that regularly occurs shortly before the next dose is due.388

Opioid ceiling doses

Use caution when prescribing opioids at any dosage. Many harms are dose related, so aim for the lowest effective dose then carefully reassess for evidence of individual benefits and risks, especially when increasing dosage to 50 mg OME or more per day. GPs must be able to justify a decision to titrate dosage to 100 mg or more OME per day and should avoid increasing dosage to 100 mg or more OME per day without specialist involvement.8 Higher opioid doses may be acceptable in cancer-related pain.


Tolerance is a predictable state of adaption in which exposure to a drug induces changes that result in diminution of one or more of the drug’s effects over time.389 The patient become ‘desensitised’ to the drug and increased doses are then needed to get the same effect.

The decrease in the effectiveness of opioid analgesia has traditionally been attributed to opioid tolerance (a desensitisation of anti-nociceptive pathways to opioids). However, it is now known that administration of opioids can also result in opioid-induced hyperalgesia (OIH), which is a sensitisation of pro-nociceptive pathways leading to pain hypersensitivity. Both tolerance and OIH can significantly reduce the analgesic effect of opioids.390,391

The predictable and physiological decrease in the effect of a drug over time may be referred to as ‘pharmacological tolerance’. ‘Apparent tolerance’ occurs when both tolerance and OIH contribute to a decrease in the effectiveness of opioids.392,393

There is some evidence that administration of ‘commonly used’ dosages of oral opioids does not result in abnormal pain sensitivity.394

In an individual patient displaying decreased effectiveness of opioid therapy, it can be impossible to determine whether tolerance or OIH is causing a reduction in pain control, creating a management dilemma: inadequate pain relief due to tolerance may improve with opioid dose escalation, while improvements in analgesia in the presence of OIH may follow a reduction in opioid dose.392 The only reasonable action in these circumstances is to reduce opioid doses.

Tolerance also occurs to some of the adverse effects of opioids. Rapid tolerance may develop to sedation, cognitive effects, nausea and respiratory depression. However, there is little, if any, change in miosis or constipation.392

‘Dependence’ has historically been defined in pharmacological terms: a time-limited state that develops during chronic drug treatment in which cessation elicits an abstinence reaction (withdrawal) and is reversed by renewed administration of the drug.157

Opioid withdrawal syndrome is characterised by signs and symptoms of sympathetic stimulation due to decreased sympathetic antagonism by opioids (Table 12).157 Symptoms start two to three half-lives after the last dose of opioid. For example, oxycodone has a half-life of 3–4 hours: symptoms would start after 6–12 hours, peak at approximately 48–72 hours, and resolve within 7–14 days.157 Timelines and symptoms vary depending on the duration of action,19 specific dose, speed of taper, and duration of use.157

Withdrawal can be minimised by gradual reduction of opioid use. Where it does occur, unless a patient has significant comorbidity or is otherwise medically unstable, withdrawal is not life threatening, although it may be very distressing.19,157 Acute withdrawal (when opioids are stopped suddenly, or an antagonist such as naloxone or naltrexone is administered) should be treated by reintroducing opioids or by IV fluids, glucose, and adrenergic-blocking drugs. Clonidine is useful in this situation.157 Reassurance and comfort measures may also be required.157

Common opioid-related adverse effects are sedation, pruritus, nausea, vomiting, slowing of gastrointestinal function and urinary retention.395–397 Uncommonly, opioids (methadone, oxycodone) are associated with prolonged QT-interval with a risk of TdP and cardiac arrest.398,399 These effects are dose related.

  1. Cohen M, Quintner J, Buchanan D. Is chronic pain a disease? Pain Med 2013;14(9):1284–88.
  2. Upshur CC, Luckmann RS, Savageau JA. Primary care provider concerns about management of chronic pain in community clinic populations. J Gen Intern Med 2006;21(6):652–55.
  3. Henderson JV, Harrison CM, Britt HC, Bayram CF, Miller GC. Prevalence, causes, severity, impact, and management of chronic pain in Australian general practice patients. Pain Med 2013;14(9):1346–61.
  4. O’Rorke JE, Chen I, Genao I, Panda M, Cykert S. Physicians’ comfort in caring for patients with chronic nonmalignant pain. Am J Med Sci 2007;333(2):93–100.
  5. Australian and New Zealand College of Anaesthetists. Recommendations regarding the use of opioid analgesics in patients with chronic non-cancer pain. Melbourne: ANZCA, 2015 PM1-2010.pdf [Accessed 19 July 2017].
  6. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924–26.
  7. Schug S, Palmer G, Scott D, et al. Acute pain management: Scientific evidence. 4th edn. Melbourne: ANZCA, 2015 Documents/APMSE4_2015_Final [Accessed 19 July 2017].
  8. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. JAMA 2016;315(15):1624–45.
  9. Saragiotto BT, Machado GC, Ferreira ML, Pinheiro MB, Abdel Shaheed C, Maher CG. Paracetamol for low back pain. Cochrane Database Syst Rev 2016(6):CD012230.
  10. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: A double-blind, randomised controlled trial. Lancet 2014;384(9954):1586–96.
  11. Moore RA, Derry S, Aldington D, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults – An overview of Cochrane reviews. Cochrane Database Syst Rev 2015(9):CD008659.
  12. Moore RA, Derry S, Wiffen PJ, Straube S, Aldington DJ. Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions. Eur J Pain 2015;19(9):1213–23.
  13. Moore RA, Derry S, Aldington D, Wiffen PJ. Adverse events associated with single dose oral analgesics for acute postoperative pain in adults – An overview of Cochrane reviews. Cochrane Database Syst Rev 2015(10):CD011407.
  14. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: A qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010;110(4):1170–79.
  15. Bailey E, Worthington HV, van Wijk A, Yates JM, Coulthard P, Afzal Z. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev 2013;12:CD004624.
  16. Shaheed CA, Maher CG, McLachlan AJ. Investigating the efficacy and safety of over-the-counter codeine containing combination analgesics for pain and codeine based antitussives. Canberra: Therapeutic Goods Association, 2016 [Accessed 19 July 2017].
  17. Blondell RD, Azadfard M, Wisniewski AM. Pharmacologic therapy for acute pain. Am Fam Physician 2013;87(11):766–72.
  18. Bendtsen L, Evers S, Linde M, et al. EFNS guideline on the treatment of tension-type headache – Report of an EFNS task force. Eur J Neurol 2010;17(11):1318–25.
  19. Thorson D, Biewen P, Bonte B, et al. Acute pain assessment and opioid prescribing protocol. Bloomington, MN: Institute for Clinical Systems Improvement, 2014 Opioids.pdf [Accessed 1 September 2017].
  20. Australian and New Zealand College of Anaesthetists. Guidelines on acute pain management. Melbourne: ANZCA, 2013 Documents/ps41-2013-guidelines-on-acute-painmanagement [Accessed 19 July 2017].
  21. Traeger AC, Hubscher M, Henschke N, Moseley GL, Lee H, McAuley JH. Effect of primary care-based education on reassurance in patients with acute low back pain: Systematic review and meta-analysis. JAMA Intern Med 2015;175(5):733–43.
  22. Qaseem A, Wilt TJ, McLean RM, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2017;166(7):514–30.
  23. Chung JW, Zeng Y, Wong TK. Drug therapy for the treatment of chronic nonspecific low back pain: Systematic review and meta-analysis. Pain Physician 2013;16(6):E685–704.
  24. van den Bekerom MP, Sjer A, Somford MP, Bulstra GH, Struijs PA, Kerkhoffs GM. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle sprains in adults: Benefits outweigh adverse events. Knee Surg Sports Traumatol Arthrosc 2015;23(8):2390–99.
  25. Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev 2010(6):CD007402.
  26. Predel HG, Giannetti B, Seigfried B, Novellini R, Menke G. A randomized, double-blind, placebo-controlled multicentre study to evaluate the efficacy and safety of diclofenac 4%
  27. spray gel in the treatment of acute uncomplicated ankle sprain. J Int Med Res 2013;41(4):1187–202.
  28. Predel HG, Hamelsky S, Gold M, Giannetti B. Efficacy and safety of diclofenac diethylamine 2.32% gel in acute ankle sprain. Med Sci Sports Exerc 2012;44(9):1629–36.
  29. Serinken M, Eken C, Turkcuer I, Elicabuk H, Uyanik E, Schultz CH. Intravenous paracetamol versus morphine for renal colic in the emergency department: A randomised double-blind controlled trial. Emerg Med J 2012;29(11):902–95.
  30. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database Syst Rev 2005(2):CD004137.
  31. Afshar K, Jafari S, Marks AJ, Eftekhari A, MacNeily AE. Nonsteroidal anti-inflammatory drugs (NSAIDs) and nonopioids for acute renal colic. Cochrane Database Syst Rev 2015(6):CD006027.
  32. Turk C, Petrik A, Sarica K, et al. EAU guidelines on diagnosis and conservative management of urolithiasis. Eur Urol 2016;69(3):468–74.
  33. Sin B, Koop K, Liu M, Yeh JY, Thandi P. Intravenous acetaminophen for renal colic in the emergency department: Where do we stand? Am J Ther 2017;24(1):e12–e19.
  34. Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MT. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2014;4:CD008509.
  35. Colli A, Conte D, Valle SD, Sciola V, Fraquelli M. Metaanalysis: Nonsteroidal anti-inflammatory drugs in biliary colic. Aliment Pharmacol Ther 2012;35(12):1370–78.
  36. National Institute for Health and Clinical Excellence. Gallstone disease: Diagnosis and initial management. NICE guidelines CG188. London: NICE, 2014. Available at www. [Accessed 21 July 2017].
  37. Zakko SF. Uncomplicated gallstone disease in adults. UpToDate, 2016 uncomplicated-gallstone-disease-in-adults?topicKey=GAST %2F654&elapsedTimeMs=5&source=machineLearning&se archTerm=biliary+colic&selectedTitle=1%7E150&view=print &displayedView=full&anchor=H25 [Accessed 21 July 2017].
  38. Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain management after thirdmolar extractions: Translating clinical research to dental practice. J Am Dent Assoc 2013;144(8):898–908.
  39. Marjoribanks J, Proctor M, Farquhar C, Derks RS.
  40. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev 2010(1):CD001751.
  41. Cunningham A, Breuer J, Dwyer D, et al. The prevention and management of herpes zoster. Med J Aust 2008;188(3):171–76.
  42. Dworkin RH, Johnson RW, Breuer J, et al.
  43. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(Suppl 1):S1–26.
  44. Dwyer DE, Cunningham AL. 10: Herpes simplex and varicella-zoster virus infections. Med J Aust 2002;177(5):267–73.
  45. Berry JD, Petersen KL. A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster. Neurology 2005;65(3):444–47.
  46. Jensen-Dahm C, Rowbotham MC, Reda H, Petersen KL.
  47. Effect of a single dose of pregabalin on herpes zoster pain. Trials 2011;12:55.
  48. Lin PL, Fan SZ, Huang CH, et al. Analgesic effect of lidocaine patch 5% in the treatment of acute herpes zoster: A double-blind and vehicle-controlled study. Reg Anesth Pain Med 2008;33(4):320–25.
  49. Chen N, Li Q, Yang J, Zhou M, Zhou D, He L. Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2014(2):CD006866.
  50. Chen N, Yang M, He L, Zhang D, Zhou M, Zhu C.
  51. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2010(12):CD005582.
  52. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: A Cochrane review. J Neurol Neurosurg Psychiatry 2010;81(12):1372–73.
  53. Moore RA, Derry S, Wiffen PJ, Straube S, Bendtsen L. Evidence for efficacy of acute treatment of episodic tensiontype headache: Methodological critique of randomised trials for oral treatments. Pain 2014;155(11):2220–28.
  54. Chaibi A, Russell MB. Manual therapies for cervicogenic headache: A systematic review. J Headache Pain 2012;13(5):351–59.
  55. Luedtke K, Allers A, Schulte LH, May A. Efficacy of interventions used by physiotherapists for patients with headache and migraine-systematic review and metaanalysis. Cephalalgia 2016;36(5):474–92.
  56. Derry S, Moore RA. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013;4:CD008040.
  57. Kirthi V, Derry S, Moore RA. Aspirin with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013;4:CD008041.
  58. Rabbie R, Derry S, Moore RA. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013;4:CD008039.
  59. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013;4:CD008783.
  60. Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral metoclopramide for acute migraine: Meta-analysis of randomised controlled trials. BMJ 2004;329(7479):1369–73.
  61. Friedman BW, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med 2008;52(4):399–406.
  62. Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995;26(5):541–46.
  63. Taggart E, Doran S, Kokotillo A, Campbell S, Villa-Roel C, Rowe BH. Ketorolac in the treatment of acute migraine: A systematic review. Headache 2013;53(2):277–87.
  64. Thorlund K, Mills EJ, Wu P, et al. Comparative efficacy of triptans for the abortive treatment of migraine: A multiple treatment comparison meta-analysis. Cephalalgia 2014;34(4):258-67.
  65. Tepper SJ. Opioids should not be used in migraine. Headache 2012;52(Suppl 1):30–34.
  66. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use and dependence among persons with migraine: Results of the AMPP study. Headache 2012;52(1):18–36.
  67. Finocchi C, Viani E. Opioids can be useful in the treatment of headache. Neurol Sci 2013;34(Suppl 1):S119–24.
  68. Broner SW, Sun-Edelstein C, Lay CL. Cluster headache in women. Curr Pain Headache Rep 2007;11(2):127–30.
  69. Finkel AG. Epidemiology of cluster headache. Curr Pain Headache Rep 2003;7(2):144–49.
  70. Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: A meta-analysis of population-based studies. Cephalalgia 2008;28(6):614–18.
  71. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P. Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database Syst Rev 2008(3):CD005219.
  72. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: A randomized trial. JAMA 2009;302(22):2451–57.
  73. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ,
  74. Schwedt TJ. Treatment of cluster headache: American Headache Society evidence-based guidelines. Headache 2016;56(7):1093–106.
  75. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P, Weibel S. Normobaric and hyperbaric oxygen therapy for the treatment and prevention of migraine and cluster headache. Cochrane Database Syst Rev 2015(12):CD005219.
  76. Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane Database Syst Rev 2013;7:CD008042.
  77. Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment of cluster headache. Neurology 2010;75(5):463–73.
  78. van der Meer HA, Speksnijder CM, Engelbert R,
  79. Lobbezoo F, Nijhuis-van der Sanden MW, Visscher CM. The association between headaches and temporomandibular disorders is confounded by bruxism and somatic complaints. Clin J Pain 2016. doi: 10.1097/ AJP.0000000000000470.
  80. Costa YM, Conti PC, de Faria FA, Bonjardim LR.
  81. Temporomandibular disorders and painful comorbidities: Clinical association and underlying mechanisms. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;123(3):288–97.
  82. Schiffman E, Ohrbach R, List T, et al. Diagnostic criteria for headache attributed to temporomandibular disorders. Cephalalgia 2012;32(9):683–92.
  83. Mujakperuo HR, Watson M, Morrison R, Macfarlane TV.
  84. Pharmacological interventions for pain in patients with temporomandibular disorders. Cochrane Database Syst Rev 2010(10):CD004715.
  85. Ta LE, Dionne RA. Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: A randomized placebo-controlled comparison of celecoxib to naproxen. Pain 2004;111(1-2):13–21.
  86. Kelley JM, Kraft-Todd G, Schapira L, Kossowsky J, Riess H. The influence of the patient-clinician relationship on healthcare outcomes: A systematic review and metaanalysis of randomized controlled trials. PLoS One 2014;9(4):e94207.
  87. National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer pain. Part B: Recommendations for practice. Ontario:
  88. NOUGG, 2010. Available at http://nationalpaincentre. [Accessed 21 July 2017].
  89. Klinger R, Colloca L, Bingel U, Flor H. Placebo analgesia: Clinical applications. Pain 2014;155(6):1055–58.
  90. Miller FG, Kaptchuk TJ. The power of context: Reconceptualizing the placebo effect. J R Soc Med 2008;101(5):222–25.
  91. Lee C, Crawford C, Swann S, Active Self-Care Therapies for Pain Working Group. Multimodal, integrative therapies for the self-management of chronic pain symptoms. Pain Med 2014;15(Suppl 1):S76–85.
  92. Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database Syst Rev 2005(3):CD000335.
  93. Fransen M, McConnell S, Harmer AR, Van der Esch M, Simic M, Bennell KL. Exercise for osteoarthritis of the knee: A Cochrane systematic review. Br J Sports Med 2015;49(24):1554–57.
  94. Fransen M, McConnell S, Hernandez-Molina G,
  95. Reichenbach S. Exercise for osteoarthritis of the hip. Cochrane Database Syst Rev 2014;4:CD007912.
  96. Busch AJ, Barber KA, Overend TJ, Peloso PM, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 2007(4):CD003786.
  97. Scottish Intercollegiate Guidelines Network. Management of chronic pain (SIGN 136). Edinburgh: SIGN, 2013 [Accessed 1 September 2017].
  98. Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012;11:CD007407.
  99. Eccleston C, Hearn L, Williams AC. Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst Rev 2015;10:CD011259.
  100. Hooten W, Timming R, Belgrade M, et al. Assessment and management of chronic pain. Bloomington, MN: Institute for Clinical Systems Improvement, 2013 c26a36d83686607ad89ee835daa3c9db3f4c.pdf [Accessed 1 September 2017].
  101. Kahan M, Mailis-Gagnon A, Wilson L, Srivastava A, National
  102. Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic noncancer pain: Clinical summary for family physicians. Part 1: General population. Can Fam Physician 2011;57(11):1257–66, e407-18.
  103. The Royal Australasian College of Physicians. Prescription opioid policy: Improving management of chronic nonmalignant pain and prevention of problems associated with prescription opioid use. Sydney: RACP, 2009.
  104. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2: Guidance. Pain Physician 2012;15(3 Suppl):S67–116.
  105. National Center for Injury Prevention and Control. Common elements in guidelines for prescribing opioids for chronic pain. NCIPC, 2014 drugoverdose/pdf/common_elements_in_guidelines_for_ prescribing_opioids-a.pdf [Accessed 21 July 2017].
  106. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014;19(6):328–35.
  107. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA. 2015;313(24):2456-73.
  108. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol 2015;14(2):162–73.
  109. Australian and New Zealand College of Anaesthetists. Statement on ‘medicinal cannabis’ with particular reference to its use in the management of patients with chronic noncancer pain (PM10). Melbourne: ANZCA, 2015 [Accessed 21 July 2017].
  110. Stacey BR, Barrett JA, Whalen E, Phillips KF, Rowbotham MC. Pregabalin for postherpetic neuralgia: Placebocontrolled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 2008;9(11):1006–17.
  111. Wang F, Ruberg SJ, Gaynor PJ, Heinloth AN, Arnold LM. Early improvement in pain predicts pain response at endpoint in patients with fibromyalgia. J Pain 2011;12(10):1088–94.
  112. Therapeutics Initiative. Benefits and harms of drugs for ‘neuropathic’ pain. Vancouver: University of British Columbia, 2015 [Accessed 21 July 2017].
  113. Hughes MA, Biggs JJ, Theise MS, Graziano K, Robbins RB, Effiong AC. Recommended opioid prescribing practices for use in chronic non-malignant pain: A systematic review of treatment guidelines. J Manag Care Med 2011;14(3):52.
  114. National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer pain. Ontario: NOUGG, 2010. Available at http://nationalpaincentre. [Accessed 21 July 2017].
  115. Deyo RA, Von Korff M, Duhrkoop D. Opioids for low back pain. BMJ 2015;350:g6380.
  116. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10(2):113–30.
  117. Fagan MJ, Chen JT, Diaz JA, Reinert SE, Stein MD. Do internal medicine residents find pain medication agreements useful? Clin J Pain 2008;24(1):35–38.
  118. Bazazi AR, Zaller ND, Fu JJ, Rich JD. Preventing opiate overdose deaths: Examining objections to takehome naloxone. J Health Care Poor Underserved 2010;21(4):1108–13.
  119. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction 2016;111(7):1177–87.
  120. Strang J, McDonald R, Alqurshi A, Royall P, Taylor D, Forbes B. Naloxone without the needle – Systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug Alcohol Depend 2016;163:16–23.
  121. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med 2009;24(6):733–38.
  122. Boudreau D, Von Korff M, Rutter CM, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf 2009;18(12):1166–75.
  123. Smith HS, Peppin JF. Toward a systematic approach to opioid rotation. J Pain Res 2014;7:589–608.
  124. The British Pain Society. Opioids for persistent pain: Good practice. London: The British Pain Society, 2010.
  125. Becker WC, Fraenkel L, Edelman EJ, et al. Instruments to assess patient-reported safety, efficacy, or misuse of current opioid therapy for chronic pain: A systematic review. Pain 2013;154(6):905–16.
  126. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: A rational approach to the treatment of chronic pain. Pain Med 2005;6(2):107–12.
  127. Jammal W, Gown G. Opioid prescribing pitfalls: Medicolegal and regulatory issues. Aust Prescr 2015;38:198–203.
  128. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010(1):CD006605.
  129. Häuser W, Bock F, Engeser P, Tölle T, Willweber-Strumpf A, Petzke F. Long-term opioid use in non-cancer pain. Dtsch Ärztebl Int 2014;111(43):732–40.
  130. Tawfic Q, Kumar K, Pirani Z, Armstrong K. Prevention of chronic post-surgical pain: The importance of early identification of risk factors. J Anesth 2017;31(3):424–31.
  131. Wylde V, Hewlett S, Learmonth ID, Dieppe P. Persistent pain after joint replacement: Prevalence, sensory qualities, and postoperative determinants. Pain 2011;152(3):566–72.
  132. Chan MT, Wan AC, Gin T, Leslie K, Myles PS. Chronic postsurgical pain after nitrous oxide anesthesia. Pain 2011;152(11):2514–20.
  133. Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008;101(1):77–86.
  134. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: Risk factors and prevention. Lancet 2006;367(9522):1618–25.
  135. Treede RD, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain 2015;156(6):1003–7.
  136. Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: A systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain 2012;28(9):819–41.
  137. Hinrichs-Rocker A, Schulz K, Jarvinen I, Lefering R, Simanski C, Neugebauer EA. Psychosocial predictors and correlates for chronic post-surgical pain (CPSP) – A systematic review. Eur J Pain 2009;13(7):719–30.
  138. Buchheit T, Van de Ven T, Shaw A. Epigenetics and the transition from acute to chronic pain. Pain Med 2012;13(11):1474–90.
  139. Mauck M, Van de Ven T, Shaw AD. Epigenetics of chronic pain after thoracic surgery. Curr Opin Anaesthesiol 2014;27(1):1–5.
  140. Wesselmann U, Baranowski AP, Borjesson M, et al.
  141. Emerging therapies and novel approaches to visceral pain. Drug Discov Today Ther Strateg 2009;6(3):89–95.
  142. Olesen AE, Farmer AD, Olesen SS, Aziz Q, Drewes AM. Management of chronic visceral pain. Pain Manag 2016;6(5):469–86.
  143. Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep 2013;17(8):356.
  144. Hauser W, Zimmer C, Felde E, Kollner V. What are the key symptoms of fibromyalgia? Results of a survey of the German Fibromyalgia Association. Schmerz 2008;22(2):176–83.
  145. Clauw DJ, Arnold LM, McCarberg BH, FibroCollaborative. The science of fibromyalgia. Mayo Clin Proc 2011;86(9):907–11.
  146. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 2017;76(2):318–28.
  147. Angel Garcia D, Martinez Nicolas I, Saturno Hernandez PJ. Clinical approach to fibromyalgia: Synthesis of evidencebased recommendations, a systematic review. Reumatol Clin 2016;12(2):65–71.
  148. Clauw DJ. Fibromyalgia: A clinical review. JAMA 2014;311(15):1547–55.
  149. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, et al. 2012 Canadian guidelines for the diagnosis and management of fibromyalgia syndrome: Executive summary. Pain Res Manag 2013;18(3):119–26.
  150. Hauser W, Thieme K, Turk DC. Guidelines on the management of fibromyalgia syndrome – A systematic review. Eur J Pain 2010;14(1):5–10.
  151. Goebel A, Barker C, Turner-Stokes L, et al. Complex regional pain syndrome in adults: UK guidelines for diagnosis, referral and management in primary and secondary care. London: RCP, 2012.
  152. Casale R, Atzeni F, Sarzi-Puttini P. The therapeutic approach to complex regional pain syndrome: Light and shade. Clin Exp Rheumatol 2015;33(1 Suppl 88):S126–39.
  153. Birklein F, O’Neill D, Schlereth T. Complex regional pain syndrome: An optimistic perspective. Neurology 2015;84(1):89–96.
  154. Borchers AT, Gershwin ME. Complex regional pain syndrome: A comprehensive and critical review. Autoimmun Rev 2014;13(3):242–65.
  155. Lohnberg JA, Altmaier EM. A review of psychosocial factors in complex regional pain syndrome. J Clin Psychol Med Settings 2013;20(2):247–54.
  156. Cossins L, Okell RW, Cameron H, Simpson B, Poole HM, Goebel A. Treatment of complex regional pain syndrome in adults: A systematic review of randomized controlled trials published from June 2000 to February 2012. Eur J Pain 2013;17(2):158–73.
  157. Goh EL, Chidambaram S, Ma D. Complex regional pain syndrome: A recent update. Burns Trauma 2017;5:2.
  158. Larochelle MR, Liebschutz JM, Zhang F, Ross-Degnan D, Wharam JF. Opioid prescribing after nonfatal overdose and association with repeated overdose: A cohort study. Ann Intern Med 2016;164(1):1–9.
  159. Zanini C, Sarzi-Puttini P, Atzeni F, Di Franco M, Rubinelli S. Building bridges between doctors and patients: The design and pilot evaluation of a training session in argumentation for chronic pain experts. BMC Med Educ 2015;15:89.
  160. Gammaitoni AR, Fine P, Alvarez N, McPherson ML, Bergmark S. Clinical application of opioid equianalgesic data. Clin J Pain 2003;19(5):286–97.
  161. NSW Therapeutic Advisory Group Inc. Preventing and managing problems with opioid prescribing for chronic noncancer pain. Sydney: NSW TAG, 2015. Available at www. practical-guidance/pain-guidance-july-2015.pdf [Accessed 26 July 2017].
  162. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ 2017;189(18):E659–E66.
  163. Windmill J, Fisher E, Eccleston C, et al. Interventions for the reduction of prescribed opioid use in chronic non-cancer pain. Cochrane Database Syst Rev 2013(9):CD010323.
  164. Nilsen HK, Stiles TC, Landro NI, Fors EA, Kaasa S, Borchgrevink PC. Patients with problematic opioid use can be weaned from codeine without pain escalation. Acta Anaesthesiol Scand 2010;54(5):571–79.
  165. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J Opioid Manag 2006;2(5):277–82.
  166. Crisostomo RA, Schmidt JE, Hooten WM, Kerkvliet JL, Townsend CO, Bruce BK. Withdrawal of analgesic medication for chronic low-back pain patients: Improvement in outcomes of multidisciplinary rehabilitation regardless of surgical history. Am J Phys Med Rehabil 2008;87(7):527–36.
  167. Younger J, Barelka P, Carroll I, et al. Reduced cold pain tolerance in chronic pain patients following opioid detoxification. Pain Med 2008;9(8):1158–63.
  168. Hooten WM, Mantilla CB, Sandroni P, Townsend CO. Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering. Pain Med 2010;11(11):1587–98.
  169. Wang H, Akbar M, Weinsheimer N, Gantz S, Schiltenwolf M. Longitudinal observation of changes in pain sensitivity during opioid tapering in patients with chronic low-back pain. Pain Med 2011;12(12):1720–26.
  170. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: Evidence and recommendations for everyday practice. Mayo Clin Proc 2015;90(6):828–42.
  171. International Association for the Study of Pain. Classification of chronic pain. 2nd edn. Washington DC: IASP, 2011 aspx?ItemNumber=1673 [Accessed 26 July 2017].
  172. Katz J, Weinrib A, Fashler SR, et al. The Toronto General Hospital Transitional Pain Service: Development and implementation of a multidisciplinary program to prevent chronic postsurgical pain. J Pain Res 2015;8:695–702.
  173. Denk F, McMahon SB, Tracey I. Pain vulnerability: A neurobiological perspective. Nat Neurosci 2014;17(2):192– 200.
  174. Eisenberger NI. The neural bases of social pain: Evidence for shared representations with physical pain. Psychosom Med 2012;74(2):126–35.
  175. Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain 2016;157:1382–86.
  176. Merskey H, Bogduk N. International Association for the Study of Pain Task Force on Taxonomy. Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. 2nd edn. Seattle: IASP Press, 1994; p. 222.
  177. Smart KM, Blake C, Staines A, Thacker M, Doody C. Mechanisms-based classifications of musculoskeletal pain: Part 3 of 3: Symptoms and signs of nociceptive pain in patients with low back (+/– leg) pain. Man Ther 2012;17(4):352–57.
  178. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1–32.
  179. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: A new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006;22(10):1911–20.
  180. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: An overview of recent guidelines. Am J Med 2009;122(10 Suppl):S22–32.
  181. Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain 2010; 149(3):573–81.
  182. Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 2000;88(1):69–78.
  183. Aranda-Villalobos P, Fernandez-de-Las-Penas C, NavarroEspigares JL, et al. Normalization of widespread pressure pain hypersensitivity after total hip replacement in patients with hip osteoarthritis is associated with clinical and functional improvements. Arthritis Rheum 2013;65(5):1262–70.
  184. Graven-Nielsen T, Wodehouse T, Langford RM, ArendtNielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012;64(9):2907–16.
  185. Kosek E, Ordeberg G. Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment. Eur J Pain 2000;4(3):229–38.
  186. Rosenquist EWK. Evaluation of chronic pain in adults. UpToDate 2016 evaluation-of-chronic-pain-in-adults?source=search_ result&search=pain%20assessment&selectedTitle=1~150 - H15544430 [Accessed 3 March 2017].
  187. Kirsh KL, Jass C, Bennett DS, Hagen JE, Passik SD. Initial development of a survey tool to detect issues of chemical coping in chronic pain patients. Palliat Support Care 2007;5(3):219–26.
  188. Flor H. Psychological pain interventions and neurophysiology: Implications for a mechanism-based approach. Am Psychol 2014;69(2):188–96.
  189. Nicholas MK, Linton SJ, Watson PJ, Main CJ, Decade of the Flags Working Group. Early identification and management of psychological risk factors (‘yellow flags’) in patients with low back pain: A reappraisal. Phys Ther 2011;91(5):737–53.
  190. Ip HY, Abrishami A, Peng PW, Wong J, Chung F. Predictors of postoperative pain and analgesic consumption: A qualitative systematic review. Anesthesiology 2009;111(3):657–77.
  191. Leeuw M, Goossens ME, Linton SJ, Crombez G, Boersma K, Vlaeyen JW. The fear-avoidance model of musculoskeletal pain: Current state of scientific evidence. J Behav Med 2007;30(1):77–94.
  192. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing numerical rating scales, verbal rating scales, and visual analogue scales for assessment of pain intensity in adults: A systematic literature review. J Pain Symptom Manage 2011;41(6):1073–93.
  193. Chen L, Vo T, Seefeld L, et al. Lack of correlation between opioid dose adjustment and pain score change in a group of chronic pain patients. J Pain 2013;14(4):384–92.
  194. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162(4):276–86.
  195. Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: A review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012;15(3 Suppl):ES67–92.
  196. Gordon A, Cone EJ, DePriest AZ, Axford-Gatley RA, Passik SD. Prescribing opioids for chronic noncancer pain in primary care: Risk assessment. Postgrad Med 2014;126(5):159–66.
  197. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects
This event attracts CPD points and can be self recorded

Did you know you can now log your CPD with a click of a button?

Create Quick log