What to do when opioids fail

Romayne Gallagher MD CCFP

Eldercare and Palliative Care Programs

Providence Health Care

Definition

• Opioid success is achieving good pain relief with manageable side effects

• Opioid failure is little or no analgesia and/or intolerable side effects

Opioid Failure Differential Diagnosis

• Pseudo-failure – not really failure

• Semi-failure – cannot relieve pain without adjuvant medication

• Outright failure – no pain relief

Pseudo-failure

• Inadequate dosing– If pain uncontrolled must increase dose by 15-

25% each titration

• Poor absorption– Short GI tract not suitable for long-acting

opioids– Elders who are emaciated will not absorb

fentanyl patch well

Pseudo-failure

• Intolerable side effects before adequate pain control– e.g. 80 year old with extensive compression

fractures resulting in chronic pain– morphine, oxycodone, methadone all resulted

in intolerable drowsiness with inadequate pain control

Opioid Metabolites

*After Smith MT. Clinical and Experimental Pharmacology and Physiology 2000

Opioid Induced NeurotoxicityOpioid Induced Neurotoxicity

• Predisposing Factors:Predisposing Factors:– High opioid dosesHigh opioid doses

– Prolonged opioid useProlonged opioid use

– Recent rapid dose escalationRecent rapid dose escalation

– DehydrationDehydration

– Renal failureRenal failure

– Advanced ageAdvanced age

– Other psychoactive drugsOther psychoactive drugs

*Daeninck PJ, Bruera E. Acta Anaesthesiol Scand. 1999*Daeninck PJ, Bruera E. Acta Anaesthesiol Scand. 1999

Management of OIN

• Rehydration

• Treat concurrent causes of delirium e.g. UTI, pneumonia

• Reduce dose if pain controlled

• Switch to a different opioid

• Intrathecal administration of opioids

Pseudo-failure

• Interindividual variation – genetic variation in opioid receptors and

metabolism

All animals received same mg/kg dose

Individualize analgesic therapy• Opioid actions and interactions are dependent upon

the genetic background of the patient.• This may involve intrinsic analgesic mechanisms

and/or pharmacokinetics/metabolism• The choice of drug is empiric. At this time, it is not

possible to predict which patients will be sensitive to which specific drugs.

• Patients may differ with regards to the necessary dose of specific drug and whether or not that drug, at a reasonable dose, is capable of relieving their pain

G. Pasternak MD, PhD Head, Molecular Neuropharmacology Memorial Sloan-Kettering Cancer Centre

Pseudo-failure

• Cognitive impairment– dementia, head injury

• Depression presenting as pain

• Total pain

• Opioid addiction in a patient with pain

Prevalence

• Depression in Primary Care 5-10%• Depression in chronic pain 24-37%• Pain symptoms in depressed pts. 65%• Depressive symptoms in pain pts. 38% (5-85%)

Neuroconnections

• Pain modulation system functions on serotonin and norepinephrine

• ?reduced pain modulation in depression• Serotonin and norepinephrine given intrathecally

block peripheral pain signals as do opioids• Neuroanatomical connections between brain

emotion-generating areas and pain modulation areas

Pain

Physical symptomsPsychological

Social

CulturalSpiritual

Suffering

Woodruff, 1999

Opioid addiction in pain patients

• Deserve to have pain adequately controlled

• Need more:– Assessment: addiction consult– Structure: contract, shorter dispensing intervals,

no prn meds, one pharmacist…– Monitoring: frequent follow up, random urine

screen, function diary, collateral info..

Semi-failure

• Neuropathic pain

– Trigeminal neuralgia

– Complex Regional Pain Syndrome

– Central post stroke pain

Evidence for the Pharmacotherapy of Neuropathic Pain

• Tricyclics NNT 1.5-3.0

• Anti-convulsant drugs NNT 2-3

• Opioids* NNT 2-3

• Gabapetinoids NNT 3-5

• Venlafaxine NNT: 4.5-5

• SSRIs NNT: 6-7

• Mexiletine NNT:10-16(NNT= # of patients treated to get 1 with a 50% pain reduction)

*Opioids avg. pain reduction across studies ~ 30% (Kalso Pain, 2004)

Canadian Pain Society: consensus statement on management of Neuropathic Pain

2007

• First line• TCA/ gabapentin/ pregabalin

• Second line• SNRI/ 5% lidocaine cream(PHN only)

• Third line• CR opioids or tramadol

• Fourth line• Cannabinoids/ methadone/ lamotrigine/ topiramate

Moderate-Severe Neuropathic Pain Treatment

• Response to monotherapy usually limited; shift to multiple drug therapy

• Opioids

• Adjuvants:– Antidepressants, selective noradrenaline and serotonin reuptake

inhibitors

– TCAs including pregabalin and gabapentin for diabetic neuropathy and postherpetic neuralgia

Davis MP. What is new in neuropathic pain? Support Care Cancer 2006;[Epub ahead of print]

Topical Treatments

• Capsaïcin cream (Zostrix®)

• Lidoderm® 5% patch (Lidoderm U.S. only)

• Xylocaïne® 10% Cream:– 10 g of xylocaine powder (Xenex®)

– 90 g Glaxal base

– q4h prn – warn re: toxicity symptoms

• NSAIDs (Pennsaid®, 5% diclofenac in Phlogel)

• Usually of benefit for peripheral nerve injuries

Other Topical Treatment Options

• 4-10% ketamine• 2-5% amitriptyline• 0.01mg clonidine (for flushing or swelling)• 2-5% carbamazepine (for burning)• 6-10% gabapentin • Use in those who do not tolerate medications orally

In…PLO Gel

Incident pain

• A type of breakthrough pain that is evoked by certain activities

• Intensity can be significantly higher than baseline pain

• Matching the intensity of the pain with dosage of opioid

Time

Incident Incident Incident

Pain

Having a steady level of enough opioid to treat the peaks of incident pain...

…will often result in excessive dosing for the periods between incidents

Sublingual sufentanil

• 10mcg-25mcg s.l.

• Onset 5 minutes, offset 30 minutes

• For use in those already on opioids

• For opioid naïve – use fentanyl 10-50mcg s.l. as is about 1/10th potency

Pressure ulcers

• Systemic opioids often result in intolerable side effects with poor analgesia

Topical Opioids

• Ischemic ulcers, pressure ulcers

• Tumors

• Exposed tissue has opioid receptors

• Morphine 1% concentration in intra-site gel

• Methadone 1% concentration in Stomahesive powder

Semi-failure

• Visceral pain– Smooth muscle spasm– e.g. bladder spasm, rectal spasm– Calcium channel blockers, nitroglycerin paste– Belladonna and opium suppositories

• Skeletal muscle contracture– Botulinum toxin

Outright failure

• No analgesia at all to a trial of every available opioid

• Extremely rare individuals

In other words……

• Vast majority of pain can be treated either partially or completely with opioids

• If pain is not responding…..– Change opioid– Adjuvant medications– Depression or other psychiatric illness– Interventional pain management?– Total pain