Managing Chronic Non-Cancer Pain: Feedback and Alternatives

1. Chronic Non Cancer Pain (CNCP)Feedback from the Oxford Advanced Pain and Symptom Management Course –July 18 Anne Hounsell, Speciality Doctor, The Rowans Hospice 6/12/18

2. Objectives • The use of opioids in CNCP-risks and benefits. • Looking at alternative management options. • An example of chronic non cancer pain –peripheral vascular disease. • As well as looking at the management of CLA (critical limb ischaemia) Appendix 1- examples of chronic pain Appendix 2 –Managing chronic pain Appendix 3 –further information on CLA Appendix 4 –some papers

3. Background Definition • Pain for > 3 months or after expected duration/recovery post injury. With a non malignant cause. Pathophysiology • Tends to be that there was disease or damage to the somatosensory nervous system • However then there is an ongoing Inappropriate response of the pain signalling pathways • Pain continues despite healing with ongoing pain signalling Who can get this pain? • Anyone really! • Many of our patients have co-morbidities and non cancer diagnoses. • Likely to increase as people live for longer.

4. EXAMPLES YOU HAVE SEEN?

5. Background Continued Examples include: 1) Patients with non –cancer conditions MND, Multisystem Atrophy, MS, Parkinson’s disease, Dementia, Cardiac failure, COPD. 2) Patients with co-morbidities Arthritis, fibromyalgia, chronic back pain, chronic regional pain syndrome etc (Also chronic constipation, pressure sores)  Further information in appendix 1

6. The use of Analgesics for CNCP We have tended to use the WHO analgesic ladder:

7. HOWEVER….. • This ladder was developed for cancer pain and has not been validated for non cancer pain. • Research has found that opioids for CNCP are often not very helpful and can be harmful

8. The Use of Opioids in General Studies: • Most of the patients on opioids in the UK have chronic non cancer pain. • There is however no evidence for the use of opioids in these patients –no better than placebo. • Recent RCT –chronic back pain –pain intensity was actually worse in the opioid group. • Data looking at QOL with long term opioids is inconclusive. • No evidence relating to a) different dosing strategies 2) short versus long acting 3) continuous versus PRN 4) opioid rotation Therefore in most patients the burdens and side effects outweigh the benefits: In most people we need to focus on opioid deprescribing

9. The Effect of Opioids vs Non Opioid Medications in Pain Related Function in Patients with Chronic Back Pain or Hip/Knee Pain from OA. The SPACE RCT. Jama Journal, 18, Krebs et al. • 12-month trial ( 240 patients) • Compared the use of opioid vs non -opioid treatment for lower back pain and OA • Outcomes: Pain related function No improvement in pain-related function over 12 months (3.4 vs 3.3 points on an 11-point scale at 12 months, respectively) Pain intensity Pain significantly better in the nonopioid group over 12 months (mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the non-opioid group (difference, 0.5 [95% CI) Medication related adverse symptoms Significantly more SE’s common in the opioid group over 12 months (overall P = 0.03)

10. POTENTIAL PROBLEMS?

11. Possible damage caused by opioid use in patients with CNCP 1)Side effects and toxicity 2)Potential for abuse and addiction 3)Potential for drug overdose and death 4) Potential drug interactions 5) Others Risks of problems Patient factors mental heath problems, alcohol misuse/non-opioid drug misuse, opioid misuse There is a strong association was demonstrated between long-term opioid use and the clustering of addictive behaviours. Drug factors High doses, multiple opioids, More potent drugs, Concurrent benzodiazepines/sedative drugs

12. 1)Possible Side Effects and Toxicity Gastrointestinal Nausea, vomiting, constipation Neurological Drowsiness, cognitive impairment (decreased attention), delirium, respiratory depression, seizures, hyperalgesia, myoclonus Autonomic Dry mouth, urinary retention, postural hypotension Cutaneous Itch, sweating

13. 1)Possible opioid side effects and toxicity continued • Testosterone deficiency –opioids suppress GNRH : • affects sexual function and mood • Can decrease bone density (and therefore risk of fractures • Can contribute to obesity • Can decrease pain control and lead to hyperalgesia. • Increase risk of MI • Increased risk of osteoporosis • 50% of men on opioids for non cancer chronic pain have osteopenia • Due to testosterone deficiency and • Via a direct effect on bones – inhibits osteoblast activity • Immunosuppression

14. 2) Potential for Abuse and Addiction OPIOID MISUSE Taking for wrong reason/not according to prescription, eg using for sleep alone, or swigging from the bottle. People with depression/other mental health problems, are more likely tp be prescribed opioids as pple say it calms them. ADDICTION Continued use with experience of harm (eg, impaired control over drug use, compulsive use, continued use despite harm, craving) Sadly not much help PAPER Review rates on opioid misuse, abuse and addiction in chronic pain-a SR and data synthesis. Pain 15,Rowles • Problematic use ranged from < 1 – 81% • Misuse - 21 – 29% • Addiction - 8 – 12% (In another paper -up to 37%) (Also noted is an increase in abuse from gabapentinoids)

15. 3) Potential for Drug Overdose and Death • Co-prescription of benzodiazepines with opioids increased the risk of overdose death 4 fold • Concomitant gabapentin use (> 900mg per day) was associated with a 60% increase in the risk of opioid-related death • Very high doses gabapentin associated with 2 fold increase • The office for national statistics 2016 – for those deaths from drug poisoning 54% involved opioids. • Overdose [HR 5.2] An increase in deaths from fentanyl

16. 4) Drug interactions Combined with the following can cause potential problem -EG: Benzodiazepines Zopiclone Antidepressants (SSRIs) Other opioids Ciprofloxacin Fluconazole Antipsychotics Methyphenidate Anticonvulsants And of course alcohol

17. 5) Others Long term opioid use outcomes-Pain 06, Eriksen, Critical Issues on Opioids for Chronic Non Cancer Pain. Epidemiological study: -228 opioid users compared with 1,678 non-opioid users -Opioids usage significantly associated with: 1)Reporting of severe pain 2)Poor self-rated health 3)Inactivity during leisure 4)Unemployment 5)Higher healthcare utilization 6) Poor health orientated quality of life 7)Motor vehicle accident [OR 1.24-1.42)

18. Despite all this……. -There are a subset of patients that might benefit from opioids (though difficult to know who) -If you are going to trial it: • 120mg morphine/day maximum (risk of harm substantially increases above this) • or use intermittently. • If no useful effect after 2-4 weeks –stop

19. Opioid De-prescribing • If no useful effect after a trial of 2-4 weeks –stop • If you do wean/stop opioids -you must provide other support • OPIOID DEPENDANCE (physical) : 1)Therefore don’t stop suddenly -opioid withdrawal syndrome : 2)anxiety, irritability, alternating chills and hot sweats, ‘wetness’ ( salivation, lacrimation, rhinorrhea, sweating), sneezing, goose flesh. 3) At the peak of withdrawal –the patient can get nausea, vomiting, abdominal cramps, insomnia and occasionally myoclonus. 4) Suggestions are to taper dose by 10% per week –but no consensus! (Cochrane library)

20. If we are trying to avoid opioids for CNCP–what other options are there?

21. Managing CNCP • Can be very difficult to manage (hence why often opioids are used) • Its complex with variable interplay between biological, psychological and social factors. • Thinking of the pathophysiology of the particular pain is important. For example there may be neuropathic/inflammatory/muscle spasm components. This can help guide medication use. • Paying particular attention to non drug management is especially important. We need to help the patient function as well as possible despite the pain. • Other aspects include PT,OT, psychology (eg chronic pain clinics) • It is important to look at function rather than pain scores. See APPENDIX  2

23. An example of chronic non cancer pain • Peripheral Vascular Disease and Ischaemic limb pain

24. Peripheral Vascular Disease • Common (12% of adult population), especially those with other co-morbidities eg DM, CKD, IHD etc • Risk factors include smoking, raised cholesterol/triglycerides, diabetes, age • FEATURES: 1. Limb pain -worse at night and wakes them up -can include phantom limb pain 2. Reduced functional status 3. +/- episodes of opioid toxicity (due to the pain being very complex to treat, as well as the patient having co-morbidities) 4. +/- episodes of delirium (due to the above and infections of ulcers)

25. Non Reconstructable Critical Limb Ischaemia • Definition 1) Chronic rest pain/ulceration/gangrene (ulcer DD) 2) Patient has proven arterial occlusive disease Fontaine and Rutherford grades are used and ABPI (< 0.5) ( RG - stage 0- asymptomatic, 1-mild claudication, 2-moderate claudication, 3 –severe claudication, 4-rest pain, 5- ischaemic ulcers of toes, 6-severe ischaemic ulcers/frank gangrene) 3) Have had multiple surgical interventions (eg revascularisation/ amputation) and been assessed by the vascular team -no option of further surgery/management • There is a 20% mortality rate within 6 months of diagnosis. • Major amputation required within 1 yr in 40% of patients • 5 year mortality > colorectal/breast/prostate cancer, stroke, MI • Has a negative impact on QOL • The level of blood flow correlates with the severity of pain ie reduced flow = increase pain

27. Treating Critical Limb Ischaemia Any experience??

28. Treating Critical Limb Ischaemia 1) Create goals • eg pain management, reduction in ulcers, improving functional status and QOL, and survival • Unfortunately currently there is no effective medical therapy 2) A MDT holistic approach is needed as well as attention to the co-morbidities Further details of diagnosis, risk factors etc are in APPENDIX 3

29. (Conservative) Management of Ischaemic Pain -1 • Little data - studies involving patient reported outcome measures do not exist! • Most research focuses on physician reported outcome measures (graft patency, survival, etc.) • Cannot recommend one medication over another. • There is a significant neuropathic element -distal axonopathy.

30. Systematic Review of Pharmacological Therapies in the Management of Ischaemic Pain in Patients with Non–reconstructable Critical Limb Ischaemia.BMJ Supportive and Palliative Care, Aug 17, onlineLaoire et al • See appendix 4 for more detail • •5 RCTs, 1 observational study • IV LIDOCAINE • • IV Lidocaine vs IV morphine sulphate • • Effect: At 15 & 30 mins mean VAS pain score lower in intervention group • • No adverse effects but only monitored for 30 mins post infusion • GABAPENTIN • • Gabapentin titrated from 300mg OD to 600mg TDS, no control • • Median pain score significantly reduced each of assessment days • • 15 patients - improved night pain & perceived QOL • • No adverse effects • Poor quality study though

31. Study continued • KETAMINE Study 1 • RCT, N=35 • IV Ketamine vs N Saline over 4 hrs (b/g opioids + haloperidol) • Outcomes: • 1) Greater pain relief at 24 hrs & 5 days post ketamine infusion • 2) improved general activity & enjoyment of life • 33% “more emotional than usual” post ketamine, 6% post placebo Study 2 • RCT, N=8 • IV Ketamine (3 different doses) vs IV Morphine (no prophylactic antipsychotic) • No stat. sign. difference at peak effect times • All had perceptual disturbances & psychotropic effects

32. Study continued BURPRENORPHINE AND EPIDURAL • N=86 • Buprenorphine 35µg/hr patch + epidural morphine/ropivacaine Vs epidural alone • Outcome: 1)Significantly lower pain scores in intervention group 2)better sleep quality 3) More SEs (drowsiness, fatigue, constipation, nausea) in control group

33. STUDY OUTCOME • Lidocaine - Promising BUT further studies needed • Gabapentin - poor study design, but widely used & well tolerated • Ketamine remains controversial! ** • Buprenorphine + epidural - effective but poor quality studies - ?reproducible effect

34. KETAMINE • Analgesic in subanaesthetic doses • Anti-inflammatory, Antidepressant, Anti-Noiceptive, NMDA antagonist • But there are multiple SEs -CV, urine toxicity, cognition/psychiatric • Weak evidence for its use in CLI • Strong evidence for its use on acute/post op pain • Some evidence for use on chronic regional pain syndrome • No papers looking at subcutaneous ketamine • For chronic cancer pain -NNT 25, NNH 6 • No standard regimen in dose, route, frequency of use • The current evidence is insufficient to assess the benefits and harms of its use

35. Managing Ischaemic Pain –Other options Others • Pregabalin (no research) • Methadone? But no studies • Midazolam -can help with neuropathic pain • Ketorolac -very end of life Non pharmacological • Spinal cord stimulation • Lumbar sympathectomy -no studies • Epidural -effective but poor quality studies GET EARLY INVOLVEMENT WITH THE SURGICAL TEAM SO THAT WE CAN SUPPORT THEM. MDT approach with vascular /chronic pain/pall care teams

36. Summary of How to Manage Ischaemic Limb Pain • No single recommendation of a pharmacological agent possible • Titrate (renally friendly) opioid • Add a neuropathic agent (gabapentin 1st line) • Consider ketamine (though cannot be recommended on current level of evidence)  

37. Summary The use of opioids in CNCP • No evidence for benefit –can even increase the pain • Risk of multiple problems : 1) GI, neurological, autonomic, cutaneous, immune, cardiac and hormonal side effects 2) Opioid toxicity 3) Misuse, addiction, overdose, drug interactions Other management options for CNCP • MultidiscipIinary - including psychology, OT, PT • Non drug methods • Analgesics An example of CNCP • Peripheral Vascular Disease • Managing ischaemic limb pain in critical limb ischaemia: • Evidence available. • Consider renally friendly opioid, gabapentin, ketamine -

38. THANKYOU! ANY QUESTIONS?

39. References • Oxford Handbook of Palliative Medicine • Google scholar • ‘ Testosterone deficiency in non cancer opioid treated patients’ Coluzzi et al, Dec 18, Journal of endocrinological investigation • British Medical Association –chronic pain –supporting safer prescribing of analgesia • NICE, SIGN, Department of public health • Opioid overdose and deaths -Kaplovitch E et al. (2015) PLoS ONE 10(8) -Gomes T et al. (2017) PLoS Med 14(10) • Faculty of pain medicine –the effectiveness of opioids for long term pain -opioid aware website • Review rates on opioid misuse, abuse and addiction in chronic pain-a SR and data synthesis. Pain. 15,Rowles

40. References continued • Addictive behaviours related to opioid use for chronic pain –a population based study. Pain 2013,Hojsted et al, 154:26 • Critical issues on opioids for chronic non cancer pain. Epidemiological study Pain 06, Eriksen • The Effectiveness and Risks of Long Term Opioid Therapy for Chronic Pain: Systematic Review for a National institutes of Health Pathway to Prevention Workshop. Annuals of Internal Medicine, 2015, 162, Chou • Wilsey et al. Pain Med 2008; 9: 1107. • Gudin et al. Postgrad Med 2013 125:115. • Fishbain et al. Pain Med 2008; 9: 444. • Chou et al. Ann Int Med 2015; 162: 276 • http://www.rcoa.ac.uk/faculty-of-pain-medicine/opioids-aware -A resource for patients and HCP to support the prescribing of opioid medication for pain. • TASC 2 (transatlantic intersociety consolidation document on the Mx of PVD) • Systematic Review of Pharmacological Therapies in the Management of Ischaemic Pain in Patients with Non–reconstructable Critical Limb Ischaemia.BMJ Supportive and Palliative Care, Aug 17, online. Laoire et al • Cochrane Library

41. APPENDIX 1 -Non malignant conditions Motor Neuron Disease • Up to 73% of patients complain of pain. • Often musculoskeletal (loss of muscle, muscle contractures, joint stiffness) • Also pressure sores Stroke • Musculoskeletal –contractures, pressure sores • 18-23% have post stroke headaches • Up to 30% have shoulder hand syndrome (oedema, pain, trophic skin changes, muscle atrophy). • 8% have central pain-especially if vascular lesion.

42. Non malignant conditions continued Parkinsons disease • Pain is common in end stage Parkinsons’ disease • Stiffness, rigidity, dystonic spasms, posture • Constipation • Pressure sores Dementia • Contractures, stiffness • Pressure sores

43. Non malignant conditions continued Multiple Sclerosis 50-60% get pain Including spasticity, trigeminal neuralgia, spasms eg in legs, Lhermittes sign (sudden pain on eg neck flexion) Headache eg cluster, retro-orbital pain due to optic neuritis, trigeminal neuralgia Dysaesthetic pain (abnormal sensation) Lower back pain Visceral pain (constipation, bladder spasms, bladder distention)

44. Non malignant conditions continued Renal Failure • > 50% of dialysis patients get severe pain • Studies have shown that the pain can be as severe as from peripheral vascular disease • Often mixture of nociceptive, neuropathic and ischaemic • Analgesic challenges as often elderly with co-morbidities • Examples of causes: 1)-Often musculoskeletal –renal osteodystrophy (altered bone turnover), osteoporosis 2)-Calciphylaxis- calcification of small blood vessels –ischaemia –very painful skin lesions and ulcers 3)-Neuropathy with dopaminergic dysfunction -restless legs and crawling sensation

45. Non malignant conditions continued Heart Failure • Chest pain –refractory angina can be distressing and debilitating COPD and other respiratory conditions Chest wall pain –Musculoskeletal, effort of breathing

46. APPENDIX 2 –Managing CNCPSIGN (Scottish Intercollegiate Guideline Networks)- General Principles -1 Initial Assessment Patient centred approach Detailed pain and biopsychosocial assessment assessment(including function, mood and QOL) Try and identify cause(s) and assess for neuropathic component Watch out for red flags (eg spinal cord compression etc)

47. SIGN -2 Management Listen, validate, educate Treat underlying cause/ contributing factors where possible. Encourage self help management Encourage patient to stay at work Encourage patient to stay active Acupuncture, TENS, heat/cold Physiotherapy, Occupational therapy Focus of living despite the pain, function and quality of life Psychological support –depression and anxiety common –viscous circle (This includes CBT –psychoeducation, relaxation, distraction, cognitive restructuring) Analgesia

48. SIGN -3 Management continued Analgesia –before prescribing: • Offer non drug strategies • Agree goals –eg increased function/increased mobility/increased QOL/reduction in pain. • Agree length of analgesic trial • Discuss side effects and significant risks • Discuss short term/long term benefits (eg potential loss of analgesic effect with time) • Avoid too much co-prescribing. Review after 2-4 weeks Set scheduled follow up.

49. Possible Analgesic agents for CNCP ORAL • Paracetamol • NSAIDS –bone and inflammatory pain • Steroidseg for pain due to tumour inflammation (affecting CNS/PNS) rapidly tapering for shoulder hand syndrome in CVA • Antispasmodics • Smooth muscle –hyoscine butylbromide, nifedipine • skeletal – tizanidine, dantrolene, baclofen, clonidine, quinine, benzodiazepines, cannabinoids, gabapentinoids. • Anti-anginalseg ISMN, Nicorandil, Nifedipine • Dopamine agonists eg L dopa, Sinemet(includes methyphenidate) –for stiffness and rigidity from PD. • Others –eg methadone

50. Analgesic options other than opioids ORAL • Neuropathic agents • Antidepressants eg amitriptyline, duloxetine, mirtazapine • Anticonvulsants eg gabapentin, pregabalin, lamotrigine, sodium valproate, carbamazepine • sodium channel blockers –eg Lidocaine • Cholinergic (or acetylcholinesterase inhibitors) drugs -eg neostigmine. • Benzodiazepines eg clonazepam • Calcitonin (and for bone pain) • Prazosin, Propanolol, phenoxubenzamine • Ketamine Useful for neuropathic pain, including TGN, central CVA pain, diabetic neuropathy