1. Opioids plus adjuvants for cancer pain: systematic review Mike Bennett Professor of Palliative Medicine Lancaster University, UK

2. Introduction

3. 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

4. Pharmacology Antidepressants (TCAs) – Inhibit presynaptic uptake of 5HT and NA – Block voltage dependent sodium channels – Nortriptyline more active at NA Antiepileptics – Gabapentinoids Block α 2 δ subunit of calcium channels and reduce excitatory neurotransmitters – Older drugs Block voltage dependent sodium channels

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

6. European Neurology 2009

7. 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

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

9. Methods

10. 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

11. 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)

12. 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)

13. Results

14. 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)

15. 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

16. Pain relief Proportion with 30% pain relief Gabapentin – Intervention 62%, Control 64% (Caraceni 2004) – 45% (Ross 2005) Amitriptyline – ‘No differences’ on 0-10 scale

17. 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

18. 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)

19. Discussion

20. 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

21. 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

24. Also…. Benefits apparent within 4-8 days for cancer patients – Little or no additional benefit after this period

25. 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

26. Thank you m.i.bennett@lancaster.ac.uk