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doi:10.1093/annonc/mdr390
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clinical practice guidelines Annals of Oncology
Table 1. Guidelines for a correct assessment of the patient with pain principles of pain management
d Inform the patients about the possible onset of pain at any
1. Assess and re-assess the pain stage of the disease both during and after diagnostic
d Causes, onset, type, site, duration, intensity, relief and temporal
interventions, in addition to as a consequence of cancer or
patterns of the pain anticancer treatments, and involve them in pain management.
d Presence of the trigger factors and the signs and symptoms
They have to be encouraged to communicate with the physician
associated with the pain
and/or the nurse about their suffering, the efficacy of therapy
d Use of analgesics and their efficacy and tolerability
and any side effects, and not to consider the analgesic opioids as
2. Assess and re-assess the patient
a therapeutic approach for dying patients [18],
d The clinical situation by means of a complete/specific physical
3. Assess and re-assess your ability to inform and to communicate with the
patient and the family recommendation
d Take time to spend with the patient and the family to understand Analgesic for chronic pain should be prescribed on a regular
their needs basis and not on as required schedule [V, D].
d Prescribe a therapy which is simple to be administered and
recommendation
The oral route of administration of the analgesic drugs should
be advocated as the first choice [IV, C].
d Assess and treat the breakthrough pain (BTP) which is
Table 4. Comparison of selected opioids for mild to moderate pain (WHO step II)
Substance Widely available Relative effectiveness Duration of Maximal daily dose Starting dose
forms and strengths compared with oral effectiveness (h) without
morphine pretreatment
Dihydrocodeine Modified-release 0.17 12 240 mg 60120 mg
tablets 6090120 mg
Codeine Tablet 153060 mg 46 360 mg 1560 mg
Tramadol Drops 100 mg/ml; 0.10.2 24 400 mg 50100 mg
capsules 50 mg
Modified-release 0.10.2 12 400 mg 50100 mg
tablets 100150200 mg
Substance Route Relative effectiveness Maximal daily dose Starting dose without
compared with oral pretreatment
morphinea
Morphine sulfate Oral 1 No upper limitb 2040 mg
Morphine i.v. 3 No upper limitb 510 mg
Oxycodone Oral 1.52 No upper limitb 20 mg
Hydromorphone Oral 7.5 No upper limitb 8 mg
Fentanyl transdermal TTS + 4c No upper limitb 12 lg/hd
Buprenorphine Oral 75 4 mg 0.4 mg
Buprenorphine i.v. 100 3 mg 0.30.6 mg
Buprenorphine transdermal TTS + 4c 140 lg/h 17.535lg/h
Methadone Oral 4812e No upper limitb 10 mg
Nicomorphine Oral 1 20 mg 5 mg
Nicomorphine i.v. 3 20 mg 5 mg
a
The relative effectiveness varies considerably in the published literature and among individual patients. Switching to another opiod should therefore be done
cautiously with a dose reduction of the newly prescribed opioid.
b
The maximal dose depends on tachyphylaxis.
c
Calculated with conversion from mg/day to lg/h.
d
Not usually used as first opioid (the 12 lg/h dose corresponds to about 30 mg of oral morphine sulfate daily).
e
Factor 4 for daily morphine doses <90 mg, factor 8 for doses 90300 mg, and 12 for >300 mg.
WHO, World Health Organization; i.v. intravenous.
The average relative potency ratio of oral to subcutaneous Buprenorphine is the safest opioid of choice in patients with
morphine is between 1:2 and 1:3 [IV, C]. chronic kidney disease stages 4 or 5 (estimated glomerular
Only a few selected patients (12%) with cancer pain, filtration rate <30 ml/min) [IV, C].
refractory to all conventional strategies and/or dose-limiting Opioid switching is a practice used to improve pain relief
analgesic-related side effects, require spinal analgesia [51]. and/or drug tolerability. Although there is no high quality
Based on the findings of Myers, Smith and Kalso [5254] and evidence to support this practice, a switch to an alternative
the documented bias of the investigation of Smith et al. [55], it opioid is to be considered in clinical practice [58]. This
is evident that the role of intraspinal opioids has not been approach requires familiarity with equianalgesic doses of the
established, and well-designed, independently funded clinical different opioids [33].
trials are required. Hydromorphone or oxycodone, in both
immediate-release and modified-release formulations for oral scheduling and titration
administration, are effective alternatives to oral morphine.
Transdermal fentanyl and transdermal buprenorphine are Opioid doses should be titrated to take effect as rapidly as
best reserved for patients whose opioid requirements are stable. possible. Titration is a process for which the dose of the opioid
They are usually the treatment of choice for patients who are is speedily modified to obtain the tailored dose which provides
adequate relief of pain with an acceptable degree of side effects.
unable to swallow, patients with poor tolerance of morphine
Normal release morphine has a short half-life and is indicated
and patients with poor compliance. Although not
during the titration phase and for treating BTP episodes. I.v.
recommended in the NCCN Clinical Practice Guidelines in
titration is indicated in patients with severe pain (Table 6) [59].
Oncology for Adult Cancer Pain [21] because it is a partial
All patients should receive round-the-clock dosing with provision
agonist, buprenorphine has a role in the analgesic therapy of of a breakthrough dose to manage transient exacerbations of pain.
patients with renal impairment and undergoing hemodialysis The breakthrough dose is usually equivalent to 1015% of the total
treatment [56, 57] where no drug reduction is necessary, daily dose. If more than four breakthrough doses per day are
buprenorphine being mainly converted in the liver to necessary, the baseline opioid treatment with a slow-release
norbuprenorphine (a metabolite 40 times less potent than the formulation has to be adapted. Opioids with a rapid onset and short
parent compound). Methadone is a valid alternative but, duration are preferred for breakthrough doses. After the titration
because of marked interindividual differences in its plasma period slow-release opioids are indicated.
half-life and duration of action, it is still considered as a drug
which should be initiated by physicians with experience and recommendation
expertise in its use. Strong opioids may be combined with Individual titration of dosages by means of normal release
ongoing use of a non-opioid analgesic (step 1). morphine administered every 4 h plus rescue doses (up to
hourly) for BTP are recommended in clinical practice [IV, C].
recommendation The regular dose of slow-release opioids can then be adjusted
In the presence of renal impairment all opioids should be used to take into account the total amount of rescue morphine
with caution and at reduced doses and frequency [IV, C]. [IV, C].
Table 6. Intravenous titration (dose finding) with morphine for severe cancer pain (Harris et al. [59]).
Study design and patient Initial morphine dosage and Subsequent dosage and route Results
population route
RCT. i.v. group: i.v. group: % of patients achieving
62 strong opioid-nave 1.5 mg bolus every Oral IR morphine satisfactory pain relief:
inpatients pain intensity 10 min until pain relief 4 hourly, on the basis of d after 1 h: i.v. group,
NRS 5 (or adverse effects). the previous 84%; oral group, 25%
Patients were Oral group: i.v. requirements. (P <0.001)
randomized to receive i.v. IR morphine 5 mg i.v.: p.o. conversion d after 12 h:
morphine (n = 31) or oral every 4 h in opioid-naive 1:1. i.v. group 97%; oral group
IR morphine (n = 31) patients. Rescue dose: the 76% (P <0.001)
10 mg in patients same dose every 1 h max. d after 24 h: i.v. group
on weak opioids. Rescue Oral group: follow the and oral group similar.
dose: the same dose every same scheme i.v. group: median
1 h max. morphine
dosage (i.v.) to achieve
pain relief: 4.5 mg
(range 1.534.5). In the
same group, mean
morphine dosage (p.o.)
after stabilization: 8.3
(range 2.530) mg.
Oral group: median
morphine dosage to
achieve pain relief: 7.2
(2.515) mg.
No significant
adverse events
IR, immediate release, i.v., intravenous; NRS, numerical rating scale; p.o., per os; RCT, randomized controlled trial.
management of opioid side effects showed complete pain relief at 1 month in 27% of the patients,
and at least 50% relief in an additional 42% of the patients at
Many patients develop adverse effects such as constipation, any time in the trials included.
nausea, vomiting, urinary retention, pruritus and central The radioisotope treatment has also been investigated in
nervous system (CNS) toxicity (drowsiness, cognitive a systematic review [62]: the results showed only weak evidence of
impairment, confusion, hallucinations, myoclonic jerks a small beneficial effect on pain control in the short and medium
andrarelyopioid-induced hyperalgesia/allodynia). In some term (16 months), with no modification of the analgesics used. A
cases a reduction in opioid dose may alleviate refractory side few RCTs, involving small numbers, have shown that radioisotopes
effects. This may be achieved by using a co-analgesic or an can relieve bone pain in patients with breast cancer [63] and lung
alternative approach such as a nerve block or radiotherapy. cancer [64], while inconsistent results were produced in patients
Other strategies include the continued use of antiemetics for with hormone-refractory prostate cancer [65].
nausea, laxatives for constipation, major tranquillizers for
confusion, and psychostimulants for drowsiness. However,
recommendation
since some of the side effects may be caused by accumulation of
toxic metabolites, switching to another opioid agonist and/or All patients with pain from bone metastases which is proving
another route may allow titration to adequate analgesia without difficult to be controlled by pharmacological therapy should be
the same disabling effects. This is especially true for symptoms evaluated by a clinical oncologist for consideration of external
of CNS toxicity such as opioid-induced hyperalgesia/allodynia beam radiotherapy or radioisotope treatment [II, B].
and myoclonic jerks [60]. Naloxone is a short-acting opioid
antagonist for i.v. use able to revert symptoms of accidental bisphosphonates and bone pain
severe opioid overdose.
Bisphosphonates (BPs) form part of the standard therapy for
hypocalcemia and the prevention of skeletal-related events in
radiotherapy some cancers. There is sufficient evidence supporting the
Radiotherapy has specific and critical efficacy in providing pain analgesic efficacy of BPs in patients with bone pain due to bone
relief caused by bone metastases. Radiotherapy also has a role in metastases [66]. However, the prescription of BPs should not
tumors compressing nerve structures and cerebral metastases. A be considered as an alternative to analgesic treatment and their
systematic review [61] on the use of radiotherapy for bone pain administration should be started after preventive dental
Substance Widely available forms and Activity Sedation Range of daily doses (mg)
strengths (mg)
Amitryptiline Tablets 2550 Antidepressive +++ 50200
Clomipramine Tablets 1075 Antidepressive (+) 50200
Nortriptyline Tablets 1025 Antidepressive + 50225
Fluoxetine Tablets 20 Antidepressive + 2080
Duloxetine Tablets 3060 Antidepressive + 60120
Carbamazepine Tablets 200400 Antiepileptic + 4001600
Gabapentin Tablets 200300400800 Antiepileptic ++ 9003600
Pregabalin Tablets 255075100150 Antiepileptic + 150600
200300 mg
Haloperidol Drops, tablets, vials Neuroleptic + 320
Chlorpromazine Drops, tablets, suppositories, Neuroleptic + 25200
vials
Usually the lowest doses of antidepressants and neuroleptics are sufficient as an adjunct to opioids unless severe depression or major psychosis has to be
treated with higher doses as appropriate.
measures [67, 68]. After the first i.v. infusions of BPs the pain antidepressant drugs or anticonvulsants (Table 7). The efficacy
can appear or its intensity increase, and the use of analgesics and tolerability of the therapy have to be monitored over time.
such as paracetamol or a basal analgesic dose increase is Steroids should be considered in the case of nerve compression.
necessary. There is evidence in adults that i.v. lidocaine and its oral analog
mexiletine are more effective than placebo in decreasing
recommendation neuropathic pain and can relieve pain in selected patients [73].
Bisphosphonates should be considered as part of the
therapeutic regimen for the treatment of patients with/without recommendation
pain due to metastatic bone disease [II, B]. Patients with neuropathic pain should be given either a tricyclic
Preventive dental measures are necessary before starting antidepressant or a anticonvulsant and subjected to side effects
bisphosphonate administration [III, A]. monitoring [I, A].
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