Opioid Treatment of Chronic Pain
Christoph Stein
Klinik für Anaesthesiologie und operative Intensivmedizin
Opioids in cancer pain
Randomized Controlled Trials
Reference
Drug
Study
characteristics
Results
Wiffen PJ et al,
Cochrane 2003
Slow vs.
Immediate
release oral
morphine
45 studies
n=3061 included
no placebo
no meta-analysis
(insufficient data)
Morphine is an effective analgesic
Slow and immediate release similar
4% discontinued because of adverse
effects
Nicholson AB,
Cochrane 2004
Methadone
vs. morphine
8 studies
n=356 included
no placebo
no meta-analysis
(insufficient data)
Similar efficacy to morphine
only single dose/short term use
Chronic non-tumor pain ?
Acetaminophen
Acetylsalicylic acid
Nonsteroidal antiinflammatory drugs
Codeine
Oxycodone
Fentanyl
Hydromorphone
Methadone
Morphine
Oxycodone
Placebo Controlled Pain Studies
• offer scientifically strongest proof
• are ethical since life is not endangered
• are ethical if rescue medication is
available
• are more ethical than exposing patients
to trials of low methodological quality or
to drugs with unproven efficacy
• minimize confounding effects of
unknown factors, expectations,
sponsoring, bias
Collier, BMJ 311:821, 1995; Jadad, Pain Clinical Updates VII(2), 1999;
Pocock, BMJ 312:125, 2000; Bell, Br J Cancer 94:1559, 2006
Moulin DE et al, Lancet 1996;347: 143-147.
Score
Morphine
(n=46)
Placebo
(n=46)
Difference
Symptom Check List-90†
67.7
67.7
0.0 (-1.9, 1.9)
Somatisation
71.1
70.3
0.8 (-1.3, 2.8)
Depression
67.1
66.9
0.2 (-2.0, 2.5)
Anxiety
62.8
63.2
-0.4 (-3.5, 2.6)
Hostility
60.9
57.9
3.0 (0.1, 5.9)
Profile of Mood States
99.6
103.2
-3.6 (-13.6, 6.4)
High sensitivity cognitive
screen
41.4
45.0
-3.6 (-8.3, 1.0)
Memory
25.1
28.3
-3.2 (-6.1, -0.1)
Language
7.0
7.3
-0.3 (-2.2, 1.7)
Attention and concentration
3.6
3.5
0.1 (-0.8, 1.0)
Self planning and regulation
3.2
3.7
-0.5 (-0.2, 1.0)
Sickness Impact Profile†
24.5
24.2
0.3 (-2.0, 2.5)
Physical dimension
16.4
15.4
1.0 (-1.2, 3.4)
Psychosocial dimension
26.5
38.1
-1.6 (-5.6, 2.4)
Pain Disability Index
44.6
45.0
-0.4 (-2.8, 2.0)
Moulin DE et al, Lancet 1996;347: 143-147.
Morphine in musculoskeletal pain
Side-effect
Morphine (%)
Placebo (%)
Both (%)
P*
Vomiting
39
2
4
0.0002
Dizziness
37
2
13
0.0004
Constipation
41
4
15
0.0005
Poor
appetite/nausea
39
7
41
0.002
Abdominal pain
22
4
7
0.04
Fatigue
22
7
11
0.10
Dry skin/itching
15
4
7
0.18
Dry mouth
17
11
24
0.58
Diarrhoea
13
13
11
0.77
Blurred vision
13
20
13
0.61
Sleeplessness
13
17
11
0.79
Confusion
9
15
4
0.55
Dose-limiting
side-effects†
28
2
28
0.003
Moulin DE et al, Lancet 1996;347:143-147.
RCTs - opioids for chronic non-cancer pain
Duration
(weeks)
Disease
Moulin et al, Lancet, 1996
6
Musculoskeletal pain
Watson et al, Neurology, 1998
4
Postherpetic neuralgia
Caldwell et al, J Rheumatol, 1999
4
Osteoarthritis
Peloso et al, J Rheumatol, 2000
4
Osteoarthritis
Huse et al, Pain, 2001
4
Phantom limb pain
Raja et al, Neurology, 2002
8
Postherpetic neuralgia
Caldwell et al, JPSM, 2002
4
Osteoarthritis
Gimbel et al, Neurology, 2003
6
Diabetic neuropathy
Watson et al, Pain, 2003
4
Diabetic neuropathy
Gilron et al, N Engl J Med, 2005
5
Diabetic/postherpetic
Chindalore et al, J Pain, 2005
3
Osteoarthritis
Khoromi et al, Pain, 2007
8
Lumbar radicular pain
Drugs and mean dosages
Reference
Study Drug
Additional
Medication
Opioid dose
Moulin DE, 1996
Morphine
Rescue
83.5 mg/d (30–120)
Watson CP, 1998
Oxycodone
Adjuvants
45 mg/d
Caldwell JR, 1999
Oxycodone
Adjuvants
40 mg/d
Peloso PM, 2000
Codeine
Rescue
318 mg/d
Huse E, 2001
Morphine
Rescue
136.6 mg/d (70–300)
Raja SN, 2002
Morphine
Methadone
Rescue
91 + 49 mg/d (15–225)
15 + 2 mg/d
Caldwell JR, 2002
Morphine
Adjuvants
30 mg/d
Gimbel JS, 2003
Oxycodone
Adjuvants
37 mg/d (10–99)
Watson CP, 2003
Oxycodone
Adjuvants
40 mg/d
Gilron I, 2005
Morphine
Gabapentin
Adjuvants
45.3 + 3.9 mg/d
Chindalore VL, 2005
Oxycodone
Naltrexone
10 – 40 mg/d
Drop-out rates
Reference
Drop Out (n)
Drop out (%)
Moulin DE, 1996
18 / 61
30 %
Watson CP, 1998
12 / 50
24 %
Caldwell JR, 1999
60 / 167
36 / 107
36 % titration
34 % RCT
Peloso PM, 2000
37 / 103
36 %
Huse E, 2001
0 / 12
3 / 12
0%
25 %
Raja SN, 2002
20 / 71
28 %, NNT 2.7
Caldwell JR, 2002
88 / 222
40 %
Gimbel JS, 2003
19 / 82
23 %
Watson CP, 2003
7 / 34
20 %, NNT 2.6
Gilron I, 2005
16 / 57
28 %
Chindalore VL, 2005
32 / 102
31 %
S3-Leitlinie
Langzeitanwendung von Opioiden bei nicht tumorbedingten
Schmerzen (LONTS)
AWMF - Nr. 041/003 www.uni-duesseldorf.de/awmf/ll/041-003.htm
Reinecke & Sorgatz. Der Schmerz 2009;5:440
Deutsche Gesellschaft zum Studium des Schmerzes (DGSS)
Deutsche Diabetes Gesellschaft (DDG),
Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin (DEGAM)
Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI)
Deutsche Gesellschaft für Angiologie (DGA)
Deutsche Gesellschaft für Gerontopsychiatrie und –psychotherapie (DGGPP)
Deutsche Gesellschaft für Neurologie (DGN)
Deutsche Gesellschaft für Osteologie (DGO)
Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie (DGOOC)
Deutsche Gesellschaft für psychologische Schmerztherapie und -forschung DGPSF
Deutsche Gesellschaft für Rheumatologie (DGRh)
Deutsche Gesellschaft für Suchtforschung und Suchttherapie (DG-Sucht)
Deutsche Gesellschaft für Urologie (DGU)
Deutsche Migräne- und Kopfschmerzgesellschaft (DMKG)
Interdisziplinäre Gesellschaft für Orthopädische und Unfallchirurgische
Schmerztherapie (IGOST)
Analgesic effects at end of treatment (20-90 days)
weighted mean differences between control and treatment groups
95% CI, n > 18.000, 60 RCT-groups
Reinecke et al. submitted
Clinically relevant pain reduction
(100 unit scale)
33%, > 20 units „clinically important“ (Farrar et al. 2001, 2003)
30%, 15-20 units „minimal important change (Ostelo et al. 2008)
26,1 units „minimal improvement“, 19,6 units „mean optimal cut off
point“ [22,9] (Fischer & Reinecke, 2008)
33% or > 22 units
(Sorgatz 2009)
8 of 10 uncontrolled studies > 3 months
do not report data on pain reduction
LONTS: strong recommendations (> 1 RCT)
1. Due to low efficacy, drug trials of max. 3 months duration are
justified only in conjunction with non-pharmacological
approaches (e.g. CBT, physiotherapy)
2. Opioid and non-opioid analgesics are equally effective.
Different side effect profiles should determine individual
therapeutic decisions (e.g. switching)
3. After 6 weeks, critical evaluation of pain reduction before
continuation of drug therapy
Fries JF, J Rheumatol 1991 (Suppl 28);18:6-10; Singh G, Am J Med 1998 (July 27): 31S
70 x 106 prescriptions
30 x 109 over the counter
mortality: 0.22 % / year
relative risk: 4.21 vs. no NSAID
NSAIDs:
Relative risk of
cardiovascular events
(myocardial infarction, stroke, death)
Trelle et al. BMJ 2011;342:c7086
Okie S, N Engl J Med
2010;363:1981-5
Diversion of analgesic drugs through family and friends
(Manchikanti & Singh, 2008)
Food and Drug Administration Rockville, MD 20857
Ajit Shetty, M.D. CEO Janssen Pharmaceutica, Inc. 1125 TrentonHarbourton Road Titusville, NJ 08560-0200
RE: NDA # 19-813
Duragesic® (fentanyl transdermal system) CII
MACMIS # 12386
WARNING LETTER
Dear Dr. Shetty,
The Division of Drug Marketing, Advertising, and Communications
(DDMAC) has reviewed a professional file card (DR-850) for
Duragesic® (fentanyl transdermal system) submitted by Janssen
Pharmaceutica, Inc. (Janssen) under cover of Form FDA 2253.
The file card makes false or misleading claims about the abuse
potential and other risks of the drug, and includes unsubstantiated
effectiveness claims for Duragesic
FDA 2009
ULTRAM® ER (tramadol HCl) Extended-Release Tablets
MACMIS # 17464
WARNING LETTER
Dear Mr. Weldon:
The Division of Drug Marketing, Advertising, and Communications
(DDMAC) has reviewed a consumer webcast video titled “Making
Sure Your Relationships Aren’t Pained When You’re In Chronic
Pain” (webcast) [02U0307B] for ULTRAM® ER (tramadol HCl)
Extended-Release Tablets (Ultram ER) submitted by Johnson &
Johnson on behalf of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Treatment goals in chronic pain
• Bio-psycho-social concept
• Multidisciplinary rehabilitation programs
•
pain, medication and use of health care
system
•
physical, psychological, occupational and
social function
Thank you!
http://anaesthesie.charite.de/
Goals for future RCT
•
•
•
•
•
•
•
•
patient satisfaction and quality of life
physical and psychological function
compare with current treatments
assess health care utilization
increase sample sizes (multicenter)
increase treatment duration
identify suitable pain syndromes
standard pain scores reported by patient only
S3 Leitlinie „Langzeitanwendung von Opioiden bei nicht
tumorbedingten Schmerzen (LONTS) AWMF - Nr. 041/003
www.uni-duesseldorf.de/awmf/ll/041-003.htm
(Reinecke & Sorgatz. Der Schmerz 2009;5:440)
Schmerzreduktion VAS (100)
Cognitive Behavioral Therapy (CBT) - Wartegruppen: 0
CBT - aktive Kontrollgruppen: 5; CBT - Behandlung: 12
NSAID-Placebo: 14; WHO II-Placebo: 15; WHO III-Placebo: 17
Klinische Relevanz
33%, > 20 SkE (Farrar et al. 2001, 2003)
30%, 15-20 SkE (Ostelo et al. 2008)
26,1 SkE: minimale Besserung, 19,6 SkE: mittlerer optimaler Cut
Off Point. [22,9] (Fischer & Reinecke, 2008)
Fazit: 33% bei > 22 SkE
Results: Opioid-Monotherapy
Functional
Improvement
(%)
VAS Pain
Reduction
(%)
Subjective
Pain Relief
(%)
Treatment
Moulin DE, 1996
0
19
2
14
4
Opioid
Placebo
Peloso PM,
2000
26
8
23
6
-
Opioid
Placebo
Huse E, 2001
0
14
7
-
Opioid
Placebo
Raja SN, 2002
0
19
2
38
11
Opioid
Placebo
Chindalore VL,
2005
P<0.05
30
23
34
26
Opioid
Placebo
WOMAC
Results: Opioids + adjuvants
Functional
Improvement
(%)
VAS Pain
Reduction
(%)
Subjective
Pain Relief
(%)
Treatment
Watson CP et al,
1998
13
19 vs. placebo
58 / 38
Opioid / Placebo
Caldwell JR et al,
1999
Not assessed
16 vs. placebo
Caldwell JR et al,
2002
0
18 / 4
23 / 14
Opioid / Placebo
Gimbel JS et al,
2003
0
27 / 15
37 / 18
Opioid / Placebo
Watson CP et al,
2003
50 / 20
47 / 21
66 / 44
Opioid / Placebo
20 / 12
80 / 31
Opioid /
Lorazepam
Gilron I et al,
2005
Pain Disability Index
43 / 14
Brief Pain Inventory
7/2
SF-36
Conclusions: Opioid Monotherapy
•
•
•
•
•
5 randomized controlled studies
max. 8 weeks treatment
20–58% drop-out rates – side effects
initial pain relief max. 17 %
initial functional improvement max. 8 %
Opioids in chronic nonmalignant pain
Functional
Improvement
(%)
Net VAS
Reduction
(%)
Subjective Pain
Relief
(%)
Treatment
Moulin, 1996
none
17 (19 - 2)
10 (14 – 4)
Opioid
Placebo
Peloso, 2000
18 (26 – 8)
17 (23 – 6)
-
Opioid
Placebo
Huse, 2001
none
7 (14 – 7)
-
Opioid
Placebo
Raja, 2002
none
17 (19 – 2 9)
27 (38 – 11)
Opioid
Placebo
Chindalore, 2005
none
1 (24 – 23)
-
Opioid
Placebo
WOMAC
Observational Studies
–
–
–
–
–
–
–
risk selection bias (no randomization)
risk outcome differences not due to treatment
may yield larger treatment effects (no placebo)
generate hypotheses
identify outcomes
suggest sample sizes
assess results from RCT in routine practice
Black, BMJ 312:125, 1996; Pocock & Elbourne, BMJ 312:125, 2000
Randomized Controlled Trials
• limitations
– sample size, restrictive exclusion criteria
– reluctance and refusal to participate
– ethical, political, legal objections
• should always be used
– when appropriate, practical and ethical
Black, BMJ 312:125, 1996
n > 18000, 3–13 weeks, 60 RCT comparisons „verum vs. placebo“
Opioids or non-opioids: 10 units VAS reduction vs. placebo (WHO I: M=8,43; CI 7,32–
9,53; WHO II: M=10,21; CI=7,23–10,19; WHO III: M=11,07; CI=5,68–16,47)
Placebo: 15 units (CI=13,24–18,06) (= 60 % of overall effect)
dropouts: 1/3 opioids, 1/4 non-opioids (lack of effect, side effects)
side effects opioids: nausea, sedation, constipation, addiction potential
NSAIDs: GI-bleeding, ulcers, thromboembolic complications
no difference between neuropathy, arthritis, back pain or compounds
opioids slightly improved functioning (11 of 14 RCT) and sleep (5 of 7 RCT) but not
quality of life
improvement by cognitive-behavioral therapy: 8 units vs. waiting list, 5 units vs. active
controls
no evidence for analgesic efficacy beyond 3 months
(10 uncontrolled studies, 2500 patients)
n > 18000, 3–13 weeks, 60 RCT comparisons „verum vs.
placebo“
Opioids or non-opioids: 10 units VAS reduction vs. placebo
(WHO I: M=8,43; CI 7,32–9,53; WHO II: M=10,21; CI=7,23–10,19;
WHO III: M=11,07; CI=5,68–16,47)
Placebo: 15 units (CI=13,24–18,06) (= 60 % of overall effect)
dropouts: 1/3 opioids, 1/4 non-opioids (lack of effect, side
effects)
side effects
opioids: nausea, sedation, constipation, addiction potential
NSAIDs: GI-bleeding, ulcers, thromboembolic complications
n > 18000, 3–13 weeks, 60 RCT comparisons „verum vs.
placebo“
no difference between neuropathy, arthritis, back pain or
compounds
opioids slightly improved functioning (11 of 14 RCT) and sleep (5
of 7 RCT) but not quality of life
improvement by cognitive-behavioral therapy (CBT):
8 units vs. waiting list, 5 units vs. active controls
no evidence for analgesic efficacy beyond 3 months
(10 uncontrolled studies, 2500 patients)