1. Prescribing for chronic non-cancer and neuropathic pain
March 2013
@MedManKeele

2. What are we covering?
The following slides provide information on analgesics for the pharmacological management of non-cancer chronic pain (including neuropathic pain), focussing on key current prescribing issues in the West Midlands.
Background
Prevalence of chronic pain
General approach to the management of chronic pain
Selection of a pharmacological agent
Paracetamol
NSAIDs
Weak opioids
Tramadol
Strong opioids
Opioid transdermal patches
Tapentadol SR
Pharmacological management of neuropathic pain
The presentation does not cover:
Management of cancer-related pain, or the use of analgesia during palliative care.

3. Background
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”.1
Chronic pain has been defined as continuous, long-term pain of more than 12 weeks or after the time that healing would have been thought to have occurred after trauma or surgery.2
Chronic pain is a subjective experience influenced and modulated by psychological factors as well as physical factors.
Chronic pain has a negative impact on general health and social and psychological well-being. It is also associated with increased mortality, particularly in those who are unable to be active.3

4. Prevalence of chronic pain
In a UK survey (2005) approximately 20% of respondents reported experiencing pain most days or every day.4
Among those reporting chronic pain on at least some days, 56% stated that it had affected their lives (e.g. time off work, less active, depressed, sex life).4
A systematic review (2013) of recent key studies on the prevalence of chronic pain found3:
chronic pain has a weighted average prevalence in adults of 20%; 7% have neuropathic pain and 7% severe pain.
chronic pain impedes activities of daily living, work and work efficiency, and reduces quality of life.
effective pain therapy (pain intensity reduction of at least 50%) results in consistent improvements in fatigue, sleep, depression, quality of life and work.

5. General approach to treatment of chronic pain
Effective treatment involves an evaluation of the cause, duration, and intensity of the pain and selection of an appropriate treatment (this may include non-drug) for the pain.
Drug treatment should be used only as part of a wider management plan aimed at improving quality of life and reducing disability.
Non-drug therapies (e.g. CBT based modalities, TENS, acupuncture and physical therapy) should be considered where appropriate.
Pharmacological measures may include paracetamol, non steroidal anti-inflammatory drugs (NSAIDs), weak opioids, strong opioids, antidepressants and anticonvulsants.
Patients should be given information and instruction about pain and pain management and be encouraged to take an active role in their pain management
Additional notes for presenters
The British Pain Society has developed patient pathways for the management of chronic pain. These are available on the Map of Medicine (available at: They cover four main areas:
Initial assessment of pain in primary care
Low back pain
Neuropathic pain
Chronic widespread pain
Local guidance and formularies should also be consulted for information on the diagnosis, management and referral of patients with pain (care pathways currently may vary from area to area according to local commissioners and local services available).
All treatment strategies need to be individualised to specific patient requirements and tolerance.

6. Selection of a pharmacological agent5
Step 1
Non-opioid (paracetamol and/or NSAID) ± adjuvant medication
Step 2
Opioid for mild to moderate pain
± non opioid (paracetamol and/or NSAID) ± adjuvant medication
Step 3
Opioid for moderate to severe pain
Persistent or increasing pain
Persistent or increasing pain
Adjuvant drugs may be considered at any step of the ladder. Choice of agent depends on the cause of pain, contraindications and adverse effects. Antidepressants or anticonvulsants may be considered for neuropathic pain.
Constipation is a long term side effect for the majority of patients taking opioids. Therefore regular laxatives should be prescribed. Encourage regular fluid intake. Antiemetics may also be required.
Review pain control and side effects regularly depending on clinical need. Consider compliance
Notes for presenters
Guidelines for the selection of therapeutic agents based on pain intensity are derived from the World Health Organization (WHO) analgesic ladder. Although this was originally devised to provide guidance on the management of cancer pain, the principles apply to the management of many other types of pain.
A patient’s treatment should be initiated at the step of the analgesic pain ladder appropriate for the severity of pain. Prescribing should be adjusted up or down the ladder as the pain severity alters. Non-opioid and adjuvant analgesics should be considered at each step of the ladder, particularly in relation to neuropathic pain. The choice of drug should be influenced by the patient’s previous experience of pain, analgesics, adverse events and preferences, co-morbidities, contraindications. Pharmacological interventions should be increased to the full therapeutic and tolerated dose before switching to a different agent.

7. Paracetamol
Paracetamol is the first line analgesic for most types of nociceptive pain
Low cost, high bioavailability, quick onset of action
Less likely to cause side effects than NSAIDs at therapeutic doses.
Several combined paracetamol and weak opioid preparations are available (e.g. co-codamol, tramacet, co-dydramol).
Reduce the scope for effective titration of the individual components
May be convenient for some patients
If combinations are used, give therapeutic doses (e.g. paracetamol 500 mg or codeine 30 mg per tablet/capsule).
Effervescent or soluble formulations contain high concentrations of sodium and are expensive. Avoid unless specific indications (e.g. difficulty swallowing).
Notes for presenters
Mild pain will often respond to paracetamol and it is the first-line analgesic for most types of nociceptive pain. Although it has a low incidence of side effects at therapeutic doses, a dose reduction may be required if the patient has hepatic impairment. For further information on contraindications, drug interactions and adverse effects of paracetamol, please see the Summary of Product Characteristics (SPC) or the British National Formulary (BNF).

8. NSAIDs
Although NSAIDs are effective analgesics for mild to moderate pain their use is limited because of adverse effects and contraindications.
NSAIDS (standard and coxibs) are associated with CV adverse outcomes, gastrointestinal adverse events and renal adverse events.6,7
Prescribing should be based on safety profiles of individual NSAIDs and individual patient risk profiles.8
If an NSAID is necessary, use ibuprofen (≤1,200 mg/day) as first line and naproxen (≤ 1,000 mg/day) as second line. Use the lowest effective dose for the shortest time necessary. Diclofenac and coxibs have a higher risk of CV adverse events.8
Osteoarthritis of the knee or hand- consider topical NSAID.8
Consider a proton pump inhibitor (e.g. omeprazole or lansoprazole) for patients requiring gastroprotection (as advised by NICE).8
Notes for presenters
Further information on NSAIDs can be found in The Medicines and Prescribing Centre (MPC) at NICE QIPP document ‘Key therapeutics topics: Medicines management options for local implementation’.

9. Weak opioids Opioids are sometimes used for chronic non-cancer pain:
Local and national prescribing guidance should be followed carefully
Benefits must be carefully balanced against the risk of tolerance, dependence, addiction and side effects.
Weaker/low potency opioids can be prescribed for patients with moderate pain in conjunction with paracetamol /NSAIDs (Step 2 of WHO analgesic ladder).
Weaker/low potency opioids include:
Codeine
Dihydrocodeine
Tramadol
Dihydrocodeine may be preferred to codeine (capacity to metabolise codeine varies considerably and many patients will not respond optimally).9

10. Tramadol
Prescribing of tramadol is increasing in the West Midlands. The number of defined daily doses increased from approx 11.3 million in 2008 to nearly 15 million in (a 31.9% increase).
Tramadol produces analgesia via two mechanism: an opioid effect and an enhancement of serotonergic and adrenergic pathways.9 Although not currently a controlled drug, it is a potent analgesic.10
Fewer typical opioid side effects BUT there are significant risks:9,11
Psychiatric reactions have been reported.
Potential to produce serotonin syndrome when prescribed with antidepressants.
Can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion.
Misuse or abuse may result in overdose and death.
Advisory Council on the Misuse of Drugs have recently recommended that the UK government should make tramadol a controlled class C substance.11
Notes for presenters
For further information on contraindications, cautions, drug interactions and adverse effects of tramadol, please see the relevant SPC or the BNF.

11. Strong opioids
Stronger opioids should only be considered at Step 3 of the pain ladder. Strong opioids should not normally be used as first line therapy for chronic pain.
Efficacy and safety of long-term strong opioid treatment for chronic non-cancer pain is uncertain (few trials have assessed this).12
Generally, if a strong opioid is required, oral morphine is the first-choice for most people because of familiarity, cost, and the available range of formulations.
Once the dose of morphine has been effectively titrated to the patient’s pain, where possible use regular dosing with modified release preparations (immediate release opioids may be associated with tolerance and problem drug abuse).
Modified release tablets and capsules should be prescribed by brand name due to variations in release profiles.13 Zomorph® capsules are currently less expensive than MST Continus® tablets.
Predictable side effects of opioids should be anticipated and managed with laxatives, anti-emetics etc. as appropriate.
Patient education is vital when prescribing strong opioids. A patient information booklet on strong opioids is a available at
Notes for presenters
Guidance on the prescribing and dispensing of controlled drugs can be found in the NPC document “A Guide to good practice in the management of controlled drugs in primary care” (
More information on adverse effects of opioids is available via the MHRA learning module on opioids. (
A useful bulletin providing prescribing and dispensing recommendations to prevent overuse of opioids has been published by Northamptonshire Primary Care Trust.

12. Strong opioid prescribing advice for chronic pain14,15
Comprehensive assessment is important. Patients with psychiatric or psychological co-morbidity will require additional support and monitoring.
Agree goals of therapy. Treatment should be reviewed at least every three months (more often if there are concerns) to ensure that it is effective and still required.
An opioid should be given at the lowest dose that gives maximal control of pain and should not be used longer than necessary. Requests for dose increases need careful evaluation.
NEVER prescribe opioid injections or pethidine for persistent non-cancer pain (unless on specialist advice).
If care is shared between hospital and community, be clear who is responsible for prescribing.

13. Strong opioid prescribing advice for chronic pain
Prescriptions should not exceed 30 days supply for Schedule 2,3 and 4 Controlled Drugs (CDs).
Ideally, within a GP practice, only one prescriber should sign repeat prescriptions for opioids.
Before a repeat prescription for an opioid is issued, recent opioid use should be assessed for evidence of over-ordering (this may indicate lack of efficacy or potential misuse).
Ensure all staff that issue repeat prescriptions are aware of which drugs are controlled drugs (CDs). If over ordering is suspected, the prescriber should be notified before a prescription is issued.
If apparent dependence is developing, consider decreasing dose steadily or issue weekly prescriptions. Put a flag on the system to prevent prescriptions being ordered too early.16

14. Opioid transdermal patches
Prescribing of opioid transdermal preparations is increasing in the West Midlands - cost and safety implications.
Fentanyl patches and buprenorphine patches are much more expensive than oral morphine at equivalent doses (see next slide).
Oral analgesics should be preferred. Patches should generally only be used in limited number of patients with stable pain (not for unstable pain) who require a strong opioid if:
Oral route is unacceptable (e.g. dysphagia, malabsorption/bowel obstruction)
Compliance problems
Intolerable side effects with morphine
If patches are considered necessary:
Initial dose should be based on patient’s opioid history.
Apply to healthy, non-hairy skin.
Temperature increases (e.g. due to fever or external heat) may increase delivery of drug causing increased side effects.9
If serious adverse events are experienced remove patches immediately and monitor for up to 24 hours after patch removal.17

15. Annual Cost Comparison
The information presented on this slide is to aid price comparison and should not be used to switch patients under any circumstances.

16. Fentanyl transdermal patches
In 2012, the West Midlands spent nearly £5 million on Fentanyl patches.
Fentanyl is a strong opioid. NOT for opioid-naïve patients. Follow MHRA safety advice.17
Reports of serious and fatal overdose from dosing errors, accidental exposure and inappropriate use of fentanyl patches.
Patches differ between brands depending on the type of patch (matrix or reservoir). Prescribe by brand.13
Fencino® and Matrifen® patches are currently the lowest cost fentanyl formulations (MIMS, March 2013).
MTRAC guidance (2012) for fentanyl patches in non cancer pain18:
Evidence for fentanyl patches is relatively weak. Cost compared with oral morphine gives it a low place in therapy.
Fentanyl patches should only be initiated by a specialist or a specialist pain management service.
Patients receiving fentanyl should be assessed frequently for efficacy of treatment, functional status improvements, compliance and adverse effects.
Additional notes for presenters
There have been reports of serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use of patches. MHRA safety advice for fentanyl patches should be followed carefully (2008).17 Some key advice is:
Healthcare professionals, particularly those who prescribe and dispense fentanyl patches, must fully inform patients and caregivers about directions for safe use: - follow the prescribed dose - follow the correct frequency of patch application - ensure that old patches are removed before applying a new one - patches must not be cut - avoid touching the adhesive side of patches and wash hands after application - follow instructions for safe storage and disposal of used or un-needed patches
Healthcare professionals, particularly those who prescribe and dispense fentanyl patches, should ensure that patients and caregivers are aware of the signs and symptoms of fentanyl overdose
Patients who experience serious adverse events should have the patches removed immediately and should be monitored for up to 24 hours after patch removal
Increased body temperature, exposure of patches to external heat source may lead to increased absorption of the drug and consequent adverse effects.
For further information on contraindications, cautions, drug interactions and adverse effects of fentanyl transdermal patches, please see the relevant SPC or the BNF.

17. Buprenorphine transdermal patches
In 2012, the West Midlands spent approx £4.2 million on buprenorphine patches .
£1.2 million on Butrans® (low dose buprenorphine, licensed for moderate, non malignant pain and similar in efficacy to co-codamol or tramadol).
MTRAC guidance (2012) for buprenorphine patches (Transtec® , Butrans®) in chronic non cancer pain:19
Buprenorphine patches should only be initiated by a specialist or a specialist pain management service.
Patients receiving buprenorphine should be assessed frequently (e.g. after two weeks) for the efficacy of treatment, improvements in functional status, compliance and adverse effects.
An RCT found low dose buprenophine (Butrans ® ) to be non-inferior to tramadol MR. A further trial found buprenorphine patches plus paracetamol to be non-inferior to co-codamol.
Costs compared with oral morphine give buprenorphine patches a low place in therapy.
Notes for presenters
For further information on contraindications, cautions, drug interactions and adverse effects of buprenorphine transdermal patches, please see the relevant SPC or the BNF.

18. Tapentadol SR
Prolonged release tapentadol (tapentadol SR) is an opioid receptor agonist and inhibitor of noradrenaline reuptake. Licensed since 2011 for severe chronic pain that can only be adequately managed with opioid analgesics.20
RCTs have found that tapentadol SR (100 mg to 250 mg bd): 21
provides comparable pain relief to oxycodone controlled release (20 to 50 mg bd) in osteoarthritis or low back pain.
is associated with better gastrointestinal tolerability than oxycodone controlled release .
Controlled release oxycodone is a high-cost comparator drug. No comparisons with lower cost opioid analgesics such as modified release morphine.
In 2011 Scottish Medicines Consortium accepted tapentadol SR for patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated.22
Notes for presenters
Tapentadol immediate release is not discussed because it is licensed only for the treatment of acute pain.
For additional information on adverse events and contraindications of Tapentadol SR, please see the relevant SPC.

19. Management of neuropathic pain23
Neuropathic pain develops as a result of damage to, or dysfunction of, the system that normally signals pain.
It may arise from a heterogeneous group of disorders that affect the peripheral and central nervous systems. Common examples include:
painful diabetic neuropathy
post-herpetic neuralgia
trigeminal neuralgia
A number of drugs are used to manage neuropathic pain including:
antidepressants
anticonvulsant drugs
opioids
topical treatments such as capsaicin and lidocaine.

20. NICE CG 96 (under review): Pharmacological treatment of neuropathic pain23
People with painful diabetic neuropathy
People with other neuropathic pain conditions
First-line treatment
Offer oral duloxetine
Offer oral amitriptyline (if duloxetine is contraindicated)
First-line treatment
Offer oral amitriptyline or pregabalin (note: many NHS bodies recommend gabapentin in preference to pregabalin)
If satisfactory pain reduction is obtained with amitriptyline but the person cannot tolerate the adverse effects, consider oral imipramine or nortriptyline as an alternative
If satisfactory pain reduction is reached continue treatment and consider gradually reducing dose over time if improvement is sustained. If unsatisfactory pain reduction at maximum tolerated dose, move to next step.
Second-line treatment
Offer treatment with another drug instead of or in combination with the original drug, after informed discussion with the person:
If first-line treatment was with duloxetine, switch to amitriptyline or pregabalin, or combine with pregabalin
If first-line treatment was with amitriptyline, switch to or combine with pregabalin
Second-line treatment
Offer treatment with another drug instead of or in combination with the original drug, after informed discussion with the person
If first-line treatment was with amitriptyline (or imipramine or nortriptyline), switch to or combine with pregabalin
If first-line treatment was with pregabalin, switch to, or combine with, amitriptyline (or imipramine or nortriptyline as an alternative if amitriptyline is effective but the person cannot tolerate the adverse effects)
Additional information for presenters
The principles of pharmacological management of neuropathic pain in a non-specialist setting is covered in NICE CG96, (2010) and is shown in the algorithm above. These guidelines are currently under review. See NICE CG96 for full details of the recommendations
NICE currently recommend oral amitriptyline or pregabalin for first line treatment of neuropathic pain for most people (note: many NHS bodies recommend gabapentin in preference to pregabalin for cost reasons- see next slide for further details). Duloxetine (or oral amitriptyline if duloxetine is contra-indicated) is recommended as the first-line treatment for painful diabetic neuropathy. If satisfactory pain relief is obtained with amitriptyline, but the patient cannot tolerate the adverse effects, imipramine or nortriptyline may be considered. If pain reduction is unsatisfactory at the maximum tolerated dose of first-line treatment, offer treatment with another drug instead of or in combination with the original drug, as shown in the algorithm above, after informed discussion with the patient. 
Start with a low dose and titrate up to an effective or maximum tolerated dose. After starting or changing treatment, perform an early clinical review of dose titration, tolerability and adverse effects to assess suitability of chosen treatment. Regularly assess pain reduction, adverse effects, daily activities and participation, mood, quality of sleep, overall improvement as reported by the person.
Patients with neuropathic pain should be referred to a specialist pain and/or a condition-specific service at any stage (including initial presentation) if pain is severe OR pain substantially limits daily activities and participation OR their underlying health condition has deteriorated
Opioids (such as morphine or oxycodone) other than tramadol should not be used for neuropathic pain without assessment by a specialist pain service or condition-specific service. Other drug treatments started by a specialist pain service or condition-specific service may continue to be prescribed in non-specialist settings, with a multidisciplinary care plan, local shared care agreements and careful management of adverse effects.
If satisfactory pain reduction is reached continue treatment and consider gradually reducing dose over time if improvement is sustained. If unsatisfactory pain reduction at maximum tolerated dose, move to next step.
Third-line treatment
Refer the person to a specialist pain service and/or a condition-specific service
While waiting for referral:
Consider oral tramadol instead of or in combination with second-line treatment. Do not use other opioids without assessment by pain clinic
Consider topical lidocaine for treatment of localised pain for people who are unable to take oral medication because of medical conditions and/or disability

21. Pregabalin or gabapentin?
Pregabalin and gabapentin are structurally related and have a similar pharmacological action and adverse events.
Limited data - no published head-to-head RCTs comparing gabapentin and pregabalin in post-herpetic neuralgia or diabetic neuropathy. One small trial in neuropathic cancer pain.
Pregabalin is much more expensive than gabapentin (see next slide)
In 2012, the NHS in West Midlands spent nearly £19 million on pregabalin . Although it has other indications, the majority of pregabalin prescriptions are for neuropathic pain. If half of the pregabalin prescriptions had been prescribed as gabapentin, this could have saved more than £8 million.
Current NICE guidance for neuropathic pain recommends pregabalin as a first line option but does not recommend gabapentin.23
NICE concluded that pregabalin is more effective than gabapentin based on indirect comparisons of the two treatments. Pregabalin vs. gabapentin, has lower number needed to treat (NNT) values for at least 30% pain reduction and 50% pain reduction.
Decision by NICE to recommend pregabalin over gabapentin has been heavily criticised because of the associated costs to the NHS; NICE have agreed to review their decision.

22. Annual cost comparison for pregabalin and gabapentin
* Doses are a guide. Gabapentin costs are based on 300 mg capsules

23. Pregabalin or gabapentin potential abuse and addiction
Cases of abuse and addiction have been reported with both pregabalin and gabapentin.24,25
Both drugs act via GABA pathways and may cause euphoria.24,25
Healthcare professionals should be aware of the possibility of abuse.
Benefits must be carefully balanced against risk and should be discussed with patients before prescribing
Frequent monitoring is important for those with a history of abuse
Be alert to over ordering of these drugs
When necessary, offer assistance with tapering off the medication.25

24. References (1)
IASP Pain Terminology. International Association for the Study of Pain
The British Pain Society.
Andrew R, Derry S, Taylor RS et al. The Costs and Consequences of Adequately Managed Chronic Non-Cancer Pain and Chronic Neuropathic Pain. Pain Pract 2013.
NOP pain poll. British Pain Society
WHO's pain ladder. World Health Organisation.
Nonsteroidal anti-inflammatory drugs (standard or coxibs) - prescribing issues Clinical Knowledge Summaries.
Non-steroidal anti-inflammatory drugs: reminder on renal failure and impairment. Drug Safety Update. Volume 2 Issue Medicines and Healthcare products Regulatory Agency.
Non-steroidal anti-inflammatory drugs. Key Therapeutics Topics: Medicines management options for local implementation’. January
British National Formulary. 64th edition. September 2012.
Opioid Analgesics: Approximate Potency Equivalence with Oral Morphine. Mims online. February
Mayor S. Drug experts call for stronger regulation of tramadol to reduce misuse. BMJ 2013;346:f1264
Manchikanti L, Ailinani H, Koyyalagunta D et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician 2011;14:
Which medicines should be considered for brand-name prescribing in primary care? From the National Electronic Library for Medicines
Opioids for persistent pain. Summary of guidance on good practice from the British Pain Society
Pain and substance misuse: improving the patient experience British Pain Society.
Guidance on the safe prescribing and dispensing controlled drugs . October Northamptonshire Primary Care Trust.
Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use. Drug Safety Update .Sept 2008, Vol 2 issue 2: 2.
Fentanyl Transdermal Patch For the treatment of chronic intractable non-cancer pain. Midlands Therapeutics Review and Advisory Committee. January

25. References (2)
Buprenorphine Transdermal Patch (Transtec® , Butrans®) for the treatment of chronic non-cancer pain . Midlands Therapeutics Review and Advisory Committee. January
Palexia SR 100 mg prolonged-release tablets . Summary of Product Characteristics Electronic Medicines Compendium.
Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician 2013;16:27-40.
Tapentadol prolonged release tablets, Resubmission. Scottish Medicines Consortium,
Neuropathic pain. CG National Institute for Health and Clinical Excellence.
Lyrica Capsules. Summary of Product Characteristics. Electronic Medicines Compendium.
Gabapentin and pregabalin: abuse and addiction. Prescrire Int 2012;21:152-4.