what else is new (pain)? - guildford advanced courses · “vitamind may constitute a safe, simple...
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What else is new (pain)?DR ANDREW DAVIES
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Introduction
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Outline
Paracetamol for cancer pain
IV paracetamol (for cancer pain)
Vitamin D for cancer pain
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Paracetamol for cancer pain
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Paracetamol
Mechanism of action:
“Uncertain”
Central action
Multiple mechanism (? interlinked)
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Paracetamol
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Paracetamol
Mechanism of action:
Serotoninergic system* – descending inhibitory pathways
Eicosanoid system (prostaglandins)
Opioid system
Cannabinoid system
Nitric oxide containing pathways
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Paracetamol
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Paracetamol
“We found no evidence that taking paracetamol together
with a morphine-like drug was better than the morphine-
type drug alone”.
Wiffen et al, 2017
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Paracetamol
Davies AN, Vriens J, Webber K, Mohammed K. An
observational study of paracetamol (acetaminophen)
deprescribing in patients with cancer pain receiving
opioids for moderate-to-severe pain. Medycyna
Paliatywna w Praktyce 2017; 11: 133-7.
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Paracetamol
“The aim of the current study was to obtain further data
about the utility of paracetamol in patients receiving
opioids for moderate-to-severe pain that are deemed to
be well pain controlled (and specifically whether or not
paracetamol can reasonably be omitted in this situation)”.
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Paracetamol
Inclusion criteria:
> 18 yr
Cancer diagnosis
Regular opioid for moderate-to-severe pain for previous
7 days
Regular oral paracetamol (i.e. ≥ 2 g / day) for previous
7 days
Average pain intensity ≤ 4/10 for previous 24 hr
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Paracetamol
Exclusion criteria:
Prognosis < 2 weeks
Cognitive impairment
Palliative radiotherapy in previous 4 weeks
New oncology therapy in previous 4 weeks
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Paracetamol
Methods:
Day 0 (face-to-face)
Brief Pain Inventory- short form (BPI-SF)
Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)
Discontinue paracetamol
Day 2 (face-to-face or telephone)
BPI-SF (pain scales)
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Paracetamol
Methods:
Day 7 (face-to-face)
BPI-SF
Question – “since stopping your paracetamol do you
feel your pain has got worse”?
Question – “since stopping your paracetamol do you
feel you have had to use more ‘breakthrough’/‘rescue’
medication”?
Question – “do you want to restart your paracetamol”?
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Paracetamol
Methods:
If the patient wanted to restart paracetamol before the
end of the study (and contacted the research team), they
were asked to complete the pain scales on the BPI-SF
before restarting the paracetamol and 48 hr after starting
the paracetamol.
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Paracetamol
44 patients randomised
40 patients completed
3 withdrawals (protocol violations)
1 death (progressive disease)
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Paracetamol
Characteristic Number of patients
(n = 44)
Aetiology pain
Cancer-related
Cancer treatment related
Unknown
42 (96%)
1 (2%)
1 (2%)
Pathophysiology of pain
Nociceptive
- somatic
- visceral
Neuropathic
Mixed
39 (88.5%)
- 27 (69%)
-12 (31%)
0 (0%)
5 (11.5%)
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Paracetamol
Results:
Patients that restarted paracetamol
18 patients (45%) – 95% CI 30-60%
11 patients restarted before end of study (median 3
days)*
7 patients restarted at end of study
*Pain scores available for 8 patients
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Paracetamol
5
4 4
5
4
2
7
4
2 2
3 3 3
2
6
1
0
1
2
3
4
5
6
7
8
9
10
Patient 5 Patient 10 Patient 15 Patient 28 Patient 30 Patient 31 Patient 39 Patient 42
Pai
n in
ten
sity
(0
-10
NR
S)
Change in average pain intensity after re-starting paracetamol
Average pain score on day of re-starting paracetamol Average pain score 2 days after re-starting paracetamol
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Paracetamol
Patient ID Worst pain –
day restarted
Worst pain –
2 days later
Least pain –
day restarted
Least pain –
2 days later
Patient 5 5 3 5 2
Patient 10 4 3 0 0
Patient 15 9 7 0 0
Patient 28 7 5 4 0
Patient 30 6 4 2 2
Patient 31 3 4 1 0
Patient 39 9 8 6 0
Patient 42 5 2 2 0
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Paracetamol
Results:
Patients that did not restart paracetamol
22 patients (55%)
However…
1 patient reported pain had got worse
2 patients reported using more rescue medication
1 patient reported both adverse effects
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Paracetamol
Results:
Restarting paracetamol was associated with “mixed”
pathophysiology (p = 0.013)
Restarting paracetamol was not associated with
demographics, aetiology of pain, baseline pain intensity
scores, baseline opioid dosage
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Paracetamol
“On the basis of these results (and those of Axelsson et al),
we would recommend a trial of discontinuing paracetamol
in all patients receiving opioids for moderate-to-severe
pain who are adequately pain controlled”.
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Paracetamol
“The patients can be assured that there is approximately a
one in two chance of not needing to restart paracetamol,
and that if they do need to start the paracetamol, pain
control can be regained within a very short period of time
(i.e. less than 48 hours)”.
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IV paracetamol (for cancer pain)
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IV paracetamol
“For patients who can take an oral dosage form, not clear
indication exists for preferential prescribing of IV
acetaminophen”.
Jibril et al, 2015
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IV paracetamol
“IV paracetamol can be used when administration PO or
PR is not possible”.
PCF6, 2017
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IV paracetamol
Potential advantages:
Non enteral route
Pharmacokinetic profile
- more predictable
- avoidance first pass metabolism
Pharmacodynamic profile
- more predictable
- faster onset of action (5-10 min for IV versus 15-30 minfor oral)
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IV paracetamol
Potential disadvantages:
IV route
- cannulation
- adverse effects (e.g. phlebitis, infection)
Health economics
- direct costs
- indirect costs
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IV paracetamol
“Morphine co-administration significantly impacts the
pharmacokinetics of oral but not intravenous paracetamol
by reducing / delaying its absorption and substantially
increasing the inter-individual pharmacokinetic variability”.
Raffa et al, 2018
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IV paracetamol
Predicted (solid blue) and observed (dashed red) pharmacokinetic profiles for a oral
and b intravenous paracetamol. Subjects received Treatment A, i.e., 4 repeat doses
of 1000 mg oral paracetamol (2 × 500 mg tablets) and an intravenous infusion of
saline every 6 h (hours 0, 6, 12, and 18), and 2 infusions of intravenous morphine
(0.125 mg/kg) at hours 6 and 12
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Vitamin D for cancer pain
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Vitamin C
“Overall, vitamin C appears
to be a safe and effective
adjunctive therapy for
acute and chronic pain
relief in specific patient
groups”.
Carr et al, 2017
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Vitamin D
“Vitamin D may constitute a
safe, simple and potentially
beneficial way to reduce
pain among patients with
vitamin D deficiency”
Helde-Frankling et al, 2017
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Vitamin D
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Vitamin D
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Vitamin D
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Vitamin D
Analgesic effects:
Analgesia variable
Effect limited to patients with low vitamin D levels
Effect related to correction of low vitamin D levels
Anti-inflammatory (PGE 2)
Modification nerve function
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Vitamin D
Bergman et al, 2015:
Observational study
100 Swedish palliative care patients
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Vitamin D
Bergman et al, 2015:
Patients with 25-hydroxyvitamin D < 50 nmol/l – mean fentanyl dose
74 mcg / hr
Patients with 25-hydroxyvitamin D > 50 nmol/l – mean fentanyl dose
43 mcg / hr (p = 0.04)
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Vitamin D
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Vitamin D
Bergman et al, 2015:
Disease stage wasn’t a confounding variable
Higher age was a confounding variable - higher age was
associated with higher 25-hydroxyvitamin D levels (in contrast to the
general population), and lower fentanyl doses
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Vitamin D
Helde-Frankling et al, 2017:
Interventional study (case control study)
78 Swedish palliative care patients
- 39 cases (low 25-hydroxyvitamin D)
- 39 matched controls (historical patients)
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Vitamin D
Helde-Frankling et al, 2017:
Cases
- > 18 yr
- “incurable” cancer
- expected survival > 1month
- 25-hydroxyvitamin D < 75 nmol/l
Vitamin D3 100 mcg/day
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Vitamin D
Helde-Frankling et al, 2017:
Matched controls (Bergman et al, 2015)
- sex
- age (+/- 10 yr)
- cancer type
- 25-hydroxyvitamin D at baseline
- survival time
- number of days in study
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Vitamin D
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Vitamin D
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Vitamin D
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Vitamin D
Helde-Frankling et al, 2017:
14 / 39 (36.0%) cases reduced fentanyl dose during study (7 patients
stopped fentanyl)
1 / 39 (2.5%) controls reduced fentanyl dose during study
11 / 11 cases that were not receiving opioids at start of study
remained opioid free at 1 month
6 / 12 controls that were not receiving opioids at start of study
remained opioid free at 1 month
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Vitamin D
Helde-Frankling et al, 2017:
“No side effects…were reported”
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Vitamin D
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Conclusion
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Conclusion
“…the path of improvementwhich I have attemptedimperfectly to indicate, wouldseem at present to lie far morein the better use of weaponslong ready in our hand, than inthe discovery of new. No onecan pretend that the formerhave hitherto been employedin other than the most feebleand half-hearted fashion”.
Mr Herbert Snow