Opioids plus adjuvants for cancer pain: systematic review

Mike BennettProfessor of Palliative Medicine

Lancaster University, UK

Introduction

Rationale• Cancer pain mechanisms

– Often mixed– Neuropathic mechanisms present in 35-39%

• Adjuvant drugs often needed – Target specific neuropathic mechanisms– Evidence supports antidepressants and antiepileptics in

non-cancer pain

Pharmacology

• Antidepressants (TCAs)– Inhibit presynaptic uptake of 5HT and NA– Block voltage dependent sodium channels– Nortriptyline more active at NA

• Antiepileptics– Gabapentinoids

• Block α2δ subunit of calcium channels and reduce excitatory neurotransmitters

– Older drugs• Block voltage dependent sodium channels

• Pain scores at end of each arm (5.7 at baseline):– placebo 4.5– gabapentin 4.2– morphine 3.7– M + GP 3.1

European Neurology 2009

In non-cancer pain– Opioids plus adjuvants are more effective than

monotherapy• Morphine plus gabapentin (Gilron 2005)• Oxycodone plus gabapentin (Hanna 2008)• Oxycodone plus pregabalin (Gatti 2009)

– Effect size• At least moderate relief

– G=61%, M=80%, MG=78%, P=31%• Good or very good relief

– G=41%, OG=56%

– Adverse effects of combinations• Generally similar to opioid alone

• What is the effectiveness of adjuvants and opioids compared to opioids alone for cancer pain?

Methods

• Search for studies that:– Had adult patients with pain from active cancer

– Prospectively compared adjuvant and opioid to opioid alone

– Used before-after, or RCT design

– Assessed pain, pain relief and adverse effects

• 8 eligible studies– 5 were RCTs– 3 ‘before-after’ designs

• Patients recruited– 465 in total, 370 (79.5%) completed study– 6 studies specified neuropathic pain– 2 had chronic cancer pain

• Drugs– Gabapentin (4)– Valproate (1), phenytoin (1)– Amitriptyline (1), imipramine (1)

• Study duration– Median 14 days (range 7 - 28 days)– 7 studies collected outcomes within 4-8 days

• Dosing– Adjuvant added to fixed opioid dose (5)– Adjuvant added to variable opioid dose (2)– Combination arm had 50% of both drugs (1)

Results

Pain• Mean additional benefit on average pain

• Significant differences

• Gabapentin– RCTs

• 0.8 points (Caraceni 2004)• 1.6 burning pain, 2.1 shooting pain (Keskinbora 2007)

– no overall pain assessment

– Observational• 1.8 points (Ross 2005)• 3.2 points (Caraceni 1999)

• Amitriptyline (RCT, Mercadante 2002)

– 0.9 points (worst pain)

• Imipramine (RCT, Walsh 1986)

– ‘pain scores similar’ but no details• significantly lower opioid doses in combination arm

• No data for valproate or phenytoin

Pain relief

• Proportion with 30% pain relief

• Gabapentin– Intervention 62%, Control 64% (Caraceni 2004)

– 45% (Ross 2005)

• Amitriptyline– ‘No differences’ on 0-10 scale

• Proportion with 50% pain relief

– Vaproate (Hardy 2001, observational)

• 27.8% , no analysis

– Phenytoin (Yajnik 1992, RCT)

• Combination = 88%• Opioid alone = 84%, no sig diff

Adverse effects• Gabapentin

– Intervention 36% (1 death and 1 resp dep), Control 17% (Caraceni 2004)

– Intervention 29%, Control 59% (Keskinbora 2007)• constipation in control arm, but most switched to oral morphine after randomisation

while intervention arm continued on fentanyl

• Phenytoin– Fewer events in intervention arm

• 50% dose reduction in combination arm

• Amitriptyline– More adverse events (drowsy and confused)

Discussion

Main findings

• Addition of adjuvant:– Significant but modest benefit on pain

• Unlikely to be greater than 1 point difference

– Increase in adverse events

– Strongest evidence supports gabapentin

But….

• 3 studies reported:– Reduced opioid +/- adjuvant doses in combination arm– Same or better pain control– Fewer adverse events in combination arm

• 5 studies reported:– Fixed doses of opioids when adjuvant added– Modest improvements in pain– More adverse events in combination arm

Also….

• Benefits apparent within 4-8 days for cancer patients– Little or no additional benefit after this period

Summary• Opioids plus adjuvants in cancer pain:

– Modest additional benefit • 1 point on 0-10 scale• In this context, NNT higher for adjuvants, NNH lower• Opioids alone are effective

– Any benefits of combination apparent within a week

• increase dose or switch if no effect at this point

– Reducing dose of opioid when adding adjuvant• Probably results in fewer adverse events for same or better pain

control

Thank you

m.i.bennett@lancaster.ac.uk