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Prescribing for chronic non-cancer and neuropathic pain

March 2013

@MedManKeelewww.pctsla.org

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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. o Backgroundo Prevalence of chronic paino General approach to the management of chronic paino Selection of a pharmacological agento Paracetamolo NSAIDso Weak opioids o Tramadolo Strong opioidso Opioid transdermal patches o Tapentadol SRo Pharmacological management of neuropathic pain

• The presentation does not cover:o Management of cancer-related pain, or the use of analgesia during

palliative care.

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sBackground

• 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

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sPrevalence 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:o chronic pain has a weighted average prevalence in adults of 20%;

7% have neuropathic pain and 7% severe pain.o chronic pain impedes activities of daily living, work and work

efficiency, and reduces quality of life.o effective pain therapy (pain intensity reduction of at least 50%)

results in consistent improvements in fatigue, sleep, depression, quality of life and work.

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sGeneral 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

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sSelection 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• ± non opioid (paracetamol and/or NSAID) ± adjuvant medication

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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

Persistent or increasing pain

Persistent or increasing pain

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sParacetamol

• Paracetamol is the first line analgesic for most types of nociceptive paino Low cost, high bioavailability, quick onset of actiono 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). o Reduce the scope for effective titration of the individual

componentso May be convenient for some patients o 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).

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sNSAIDs

• 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

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sWeak opioids

• Opioids are sometimes used for chronic non-cancer pain: o Local and national prescribing guidance should be followed

carefullyo 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:o Codeineo Dihydrocodeineo Tramadol

• Dihydrocodeine may be preferred to codeine (capacity to metabolise codeine varies considerably and many patients will not respond optimally).9

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sTramadol

• 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 2012 (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

o Psychiatric reactions have been reported.o Potential to produce serotonin syndrome when prescribed with

antidepressants.o Can be sought by drug abusers and people with addiction disorders and

may be subject to criminal diversion.o 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

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sStrong 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. o 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).

o 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 http://www.britishpainsociety.org/book_opioid_patient.pdf

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sStrong 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.

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sStrong 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

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sOpioid 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:o Oral route is unacceptable (e.g. dysphagia, malabsorption/bowel

obstruction)o Compliance problemso Intolerable side effects with morphine

• If patches are considered necessary:o Initial dose should be based on patient’s opioid history.o Apply to healthy, non-hairy skin.o Temperature increases (e.g. due to fever or external heat) may increase

delivery of drug causing increased side effects.9

o If serious adverse events are experienced remove patches immediately and monitor for up to 24 hours after patch removal.17

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sAnnual Cost Comparison

Transtec patch 70mcg/hr or equivalent

Transtec patch 52.5mcg/hr or equivalent

Transtec patch 35mcg/hr or equivalent

Butrans patch 20mcg/hr or equivalent

Butrans patch 10mcg/hr or equivalent

Butrans patch 5mcg/hr or equivalent

£0 £100 £200 £300 £400 £500 £600 £700 £800 £900

£822

£617

£411

£747

£410

£229

£286

£202

£143

£84

£42

£42

Morphine (Zomorph®) Buprenorphine patches

Fentanyl patch 100mcg/hr or equivalent

Fentanyl patch 75mcg/hr or equivalent

Fentanyl patch 50mcg/hr or equivalent

Fentanyl patch 25mcg/hr or equivalent

Fentanyl patch 12mcg/hr or equivalent

£0 £200 £400 £600 £800 £1,000 £1,200

£991

£804

£576

£576

£216

£709

£298

£197

£101

£42

Morphine (Zomorph®) Fentanyl patches

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

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sFentanyl 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

o 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

o Fencino® and Matrifen® patches are currently the lowest cost fentanyl formulations (MIMS, March 2013).

• MTRAC guidance (2012) for fentanyl patches in non cancer pain18:o Evidence for fentanyl patches is relatively weak. Cost compared with oral

morphine gives it a low place in therapy. o Fentanyl patches should only be initiated by a specialist or a specialist

pain management service. o Patients receiving fentanyl should be assessed frequently for efficacy of

treatment, functional status improvements, compliance and adverse effects.

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sBuprenorphine transdermal patches

• In 2012, the West Midlands spent approx £4.2 million on buprenorphine patches .o £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

o Buprenorphine patches should only be initiated by a specialist or a specialist pain management service.

o 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.

o 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.

o Costs compared with oral morphine give buprenorphine patches a low place in therapy.

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sTapentadol 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

o provides comparable pain relief to oxycodone controlled release (20 to 50 mg bd) in osteoarthritis or low back pain.

o 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

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sManagement 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:o painful diabetic neuropathyo post-herpetic neuralgiao trigeminal neuralgia

• A number of drugs are used to manage neuropathic pain including:o antidepressantso anticonvulsant drugso opioidso topical treatments such as capsaicin and lidocaine.

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sNICE CG 96 (under review): Pharmacological

treatment of neuropathic pain23 20

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

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

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

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)

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.

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.

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sPregabalin 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)o 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 o 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.

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sAnnual cost comparison for pregabalin

and gabapentin22

Gabapentin 300 mg tds(generic capsules)

Gabapentin 600 mg tds*(generic capsules)

Gabapentin 900 mg tds*(generic capsules)

Pregabalin 75 mg bd(Lyrica®)

Pregabalin 150 mg bd(Lyrica®)

Pregabalin 300 mg bd(Lyrica®)

£0 £100 £200 £300 £400 £500 £600 £700 £800 £900

£42.38

£84.75

£127.13

£839.50

£839.50

£839.50

Annual Cost per Patient* Doses are a guide. Gabapentin costs are based on 300 mg capsules

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sPregabalin 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. o Benefits must be carefully balanced against risk and should be

discussed with patients before prescribingo Frequent monitoring is important for those with a history of abuseo Be alert to over ordering of these drugs

• When necessary, offer assistance with tapering off the medication.25

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sReferences (1)

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1) IASP Pain Terminology. International Association for the Study of Pain. 2009. http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions&Template=/CM/HTMLDisplay.cfm&ContentID=1728

2) The British Pain Society. http://www.britishpainsociety.org/media_faq.htm

3) 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.

4) NOP pain poll. British Pain Society. 2005 . http://www.britishpainsociety.org/media_surveys.htm

5) WHO's pain ladder. World Health Organisation. http://www.who.int/cancer/palliative/painladder/en/

6) Nonsteroidal anti-inflammatory drugs (standard or coxibs) - prescribing issues. 2011 Clinical Knowledge Summaries. http://www.cks.nhs.uk/nsaids_prescribing_issues/in_the_right_clinical_topic

7) Non-steroidal anti-inflammatory drugs: reminder on renal failure and impairment. Drug Safety Update. Volume 2 Issue 10. 2009 Medicines and Healthcare products Regulatory Agency. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON088004

8) Non-steroidal anti-inflammatory drugs. Key Therapeutics Topics: Medicines management options for local implementation’. January 2013 http://publications.nice.org.uk/non-steroidal-anti-inflammatory-drugs-ktt13/options-for-local-implementation

9) British National Formulary. 64th edition. September 2012.

10) Opioid Analgesics: Approximate Potency Equivalence with Oral Morphine. Mims online. February 2013 http://www.mims.co.uk/news/1146201/Opioid-Analgesics-Approximate-Potency-Equivalence-Oral-Morphine

11) Mayor S. Drug experts call for stronger regulation of tramadol to reduce misuse. BMJ 2013;346:f1264

12) 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;14:91-121.

13) Which medicines should be considered for brand-name prescribing in primary care? From the National Electronic Library for Medicines. 2011 www.nelm.nhs.uk

14) Opioids for persistent pain. Summary of guidance on good practice from the British Pain Society. 2010 http://www.britishpainsociety.org/book_opioids_recommendations.pdf

15) Pain and substance misuse: improving the patient experience. 2007. British Pain Society. http://www.britishpainsociety.org/book_drug_misuse_main.pdf

16) Guidance on the safe prescribing and dispensing controlled drugs . October 2012. Northamptonshire Primary Care Trust. http://www.neneccg.nhs.uk/resources/uploads/files/TP%20Extra%20Safe%20Prescribing%20and%20Dispensing%20of%20CDs.pdf

17) Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use. Drug Safety Update .Sept 2008, Vol 2 issue 2: 2. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087796

18) Fentanyl Transdermal Patch For the treatment of chronic intractable non-cancer pain. Midlands Therapeutics Review and Advisory Committee. January 2012 http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Fentanyl%20TD%20SUM%206.pdf

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sReferences (2)

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19) Buprenorphine Transdermal Patch (Transtec® , Butrans®) for the treatment of chronic non-cancer pain . Midlands Therapeutics Review and Advisory Committee. January 2012 http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/esca/Bupren%20SUM5.pdf

20) Palexia SR 100 mg prolonged-release tablets . Summary of Product Characteristics. 2011 Electronic Medicines Compendium. http://www.medicines.org.uk/EMC/medicine/24390/SPC/Palexia+SR+100+mg+prolonged-release+tablets/#INDICATIONS

21) Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician 2013;16:27-40.

22) Tapentadol prolonged release tablets, Resubmission. Scottish Medicines Consortium, 2011 http://www.scottishmedicines.org.uk/files/advice/tapentadol_Palexia_SR_RESUBMISISON_FINAL_MAY_2011_for_website.pdf

23) Neuropathic pain. CG96. 2010 National Institute for Health and Clinical Excellence. http://www.nice.org.uk/CG96

24) Lyrica Capsules. Summary of Product Characteristics. Electronic Medicines Compendium. http://www.medicines.org.uk/EMC/medicine/14651/SPC/Lyrica+Capsules/

25) Gabapentin and pregabalin: abuse and addiction. Prescrire Int 2012;21:152-4.