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21.05.2013: Management of cancer pain: esmo clinical practice guidelines
Incidence of painAccording to a systematic review of the
literature, pain prevalence ranges from 33% in patients after curative
treatment to 59% in patients on anticancer treatment and to 64% in
patients with metastatic, advanced or terminal phase [1]. No difference
in pain prevalence was found between patients undergoing anticancer
treatment and those in an advanced or terminal phase of the disease [1].
Factors influencing the development of chronic pain in cancer survivors
who have completed treatment include peripheral neuropathy due
tochemotherapy, radiation-induced brachial plexopathy, chronic pelvic
pain secondary to radiation and postsurgical pain [2]. Pain has a high
prevalence in specific cancer types such as pancreatic (44%) and head
and neck cancer (40%) [3].
Moreover, another systematic review of the literature showed that nearly
half of cancer patients were under-treated, with a high variability
across study designs and clinical settings [4]. Recent studies conducted
both in Italy and pan European [5, 6] confirmed these data, showing
that different types of pain or pain syndromes [7, 8] were present in
all phases of cancer (early and metastatic) (Table 1) and were not
adequately treated in a significant percentage of patients, ranging from
56% to 82.3%. In a prospective study [9], the adequacy of analgesic
care of cancer patients was assessed by means of the Pain Management
Index in 1802 valid cases of in- and outpatients with
advanced/metastatic solid tumors enrolled at centers specifically
devoted to cancer and/or pain management (oncology/pain/palliative
centers or hospices). The study showed that, even in these centers,
patients were still classified as potentially under-treated in
9.8%–55.3% of the cases.
Contrary to the percentage of incidence of pain reported in hematologic
patients in past literature, a significant proportion of patients with
lymphoma and leukemia may suffer from pain not only in the last months
of life (83%) [5, 10], but also at the time of diagnosis and during
active treatment [10].
Despite published guidelines and educational programs on the assessment
and treatment of cancer-related pain, in any stage of oncological
disease, unrelieved pain continues to be a substantial worldwide public
health concern in patients with either solid or hematological
malignancies. Cancer-related painmay be presented as a major issue of
healthcare systems worldwide if we consider that the incidence of cancer
was 12.667.470 new cases in 2008 and, based on projections, it will be
>15 million in 2020 [11].
Assessment of patients with painInitial and ongoing assessment
of pain and of patients with pain at any disease stage should clarify
both the need for additional comprehensive evaluation and a rational
plan of care. Table 2 presents the guidelines for the adequate
assessment of patients with pain. The proper and regular selfreporting
assessment of pain intensity (PI) with the help of validated assessment
tools is the first step towards effective and individualized treatment.
The most frequently used standardized scales [12] are reported in Figure
1 and are visual analogue scales (VAS), the verbal rating scale (VRS)
and the numerical rating scale (NRS).
The assessment of the quality of pain improves the choice of the
therapy: pain is termed nociceptive when it is caused by ongoing tissue
damage, either somatic or visceral or neuropathic, if sustained by
damage or dysfunction in the nervous system (Table 1) [2]. According to
the literature, most patients with advanced cancer have at least two
types of cancer-related pain which derives from a variety of etiologies
[7, 10]. Sixty-nine percent of patients rate their worst pain at a level
that impaired their ability to function [13].
Recommendation.The intensity of pain and the treatment outcomes
should be regularly assessed using (i) VAS, or (ii) VRS or (iii) the
NRS [V, D].
In older age, the presence of limited communicative skills or of
cognitive impairment such as during the last days of life makes
self-reporting of pain more difficult, although there is no evidence of
clinical reduction in pain-related suffering. When cognitive deficits
are severe, observation of pain-related behaviors and discomfort (i.e.
facial expression, body movements, verbalization or vocalizations,
changes in interpersonal interactions, changes in routine activity) is
an alternative strategy for assessing the presence of pain (but not
intensity) [14–17]. Different observational scales are available in the
literature [16] but none of them is validated in different languages.
Assessment and management of pain in children are not considered in this
manuscript because WHO guidelines on ‘the pharmacological treatment of
persisting pain in children with medical illness’ are available.
Recommendation.Observation of pain-related behaviors and
discomfort is indicated in patients with cognitive impairment to assess
the presence of pain (expert and panel consensus).
Psychosocial distress has to be assessed because it is strongly
associated with cancer pain [18]. In fact, psychological distress may
amplify the perception of pain-related distress and similarly,
inadequately controlled pain may cause substantial psychological
distress.
Recommendation.The assessment of all components of suffering such as psychosocial distress should be considered and evaluated [II, B].
Principles of pain managementInform the patients about the
possible onset of pain in any stage of the disease, both during and
after diagnostic interventions and as a consequence of cancer or
anticancer treatments, and involve them in pain management. Patients
must be encouraged to communicate with the physician and/or the nurse
about their suffering, the efficacy of therapy and side effects and to
not consider analgesic opioids as a therapeutic approach for dying
patients [19], thus contributing to reduce opioidophobia. Patient
involvement in pain management improves communication and has a
beneficial effect on patients’ pain experience [20].
RecommendationPatients should be informed about pain and pain
management and be encouraged to take an active role in their pain
management [II, B].
• Prevent the onset of pain by means of ‘by the clock’ administration,
taking into account the half-life, bioavailability and duration of
action of different drugs.
RecommendationAnalgesic for chronic pain should be prescribed on a regular basis and not on an ‘as required’ schedule [V, D].
• Prescribe a therapy which can be administered simply and easily
managed by the patients themselves and their families, especially when
the patient is cared for at home. The oral route appears to be the most
suitable to meet this requirement, and, if well tolerated, it must be
considered as the preferred route of administration [21–26].
RecommendationThe oral route of administration of analgesic drugs should be advocated as the first choice [IV, C].
• Assess and treat breakthrough pain (BTP) defined as ‘a transitory
flare of pain that occurs on a background of relatively well controlled
baseline pain’ [27]. Typical BTP episodes are of moderate to severe
intensity, rapid in onset(minutes) and relatively short in duration
(median 30 min) [27].
RecommendationRescue dose of medications (as required or prn) other than the regular basal therapy must be prescribed for BTP episodes [V, D].
• Tailor the dosage, the type and the route of drugs administered
according to each patient’s needs. The type and dose of analgesic drugs
are influenced by the intensity of pain and have to be promptly adjusted
to reach a balancebetween pain relief and side effects. The rescue
doses (prn) taken by the patients are an appropriate measure of the
daily titration of the regular doses. An alternative route for opioid
administration should be considered when oral intake is not possible
because of severe vomiting, bowel obstruction, severe dysphagia or
severe confusion, as well as in the presence of poor pain control which
requires rapid dose escalation and/or in the presence of oral
opioid-related adverse effects.
Pain managementIn 1986, the World Health Organization (WHO)
proposed a strategy for cancer pain treatment based on a sequential
three-step analgesic ladder from non opioids to weak opioids to strong
opioids according to PI [28]. Twenty years after the publication of the
first edition [21], the WHO cancer pain relief program remains the
reference point for pain management. According to WHO guidelines, opioid
analgesics are the mainstay of analgesic therapy and are classified
according to their ability to control pain from mild to mild–moderate to
moderate–severe intensity [25, 29–31].
Opioid analgesics may be combined with nonopioid drugs such as
paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) (Algorithm
1) and with adjuvant drugs [32, 33].
RecommendationThe analgesic treatment should start with drugs
indicated by the WHO analgesic ladder appropriate for the severity of
pain [II, B].
Pain should already be managed during the diagnostic evaluation. Most
cancer patients can attain satisfactory relief of pain through an
approach that incorporates primary antitumor treatments, systemic
analgesic therapy and other noninvasive techniques such as psychological
or rehabilitative interventions.
Treatment of mild painNonopioid analgesics such as
acetaminophen/paracetamol or an NSAID are indicated for the treatment of
mild pain. NSAIDs are superior to placebo in controlling cancer pain in
single dose studies. Paracetamol and NSAIDS are universally accepted as
part of the treatment of cancer pain at any stage of the WHO analgesic
scale. There is no evidence to support superior safety or efficacy of
one NSAID over any other [34]. In a randomized clinical trial (RCT)
carried out in a small sample of cancer patients on a strong opioid
regimen,paracetamol improved pain and well-being [35]. A recent
systematic review of the literature shows that the addition of an NSAID
to WHO Step III opioids can improve analgesia or reduce opioid dose
requirement [36].
It is mandatory to periodically monitor and revise the longterm use of
NSAIDs or cyclo-oxygenase-2 (COX-2) selective inhibitors [37] because
they can induce severe toxicity such as: gastrointestinal bleeding,
platelet dysfunction and renal failure. COX-2 selective inhibitors may
increase the risk of thrombotic cardiovascular adverse reactions [38]
and do not offer protection from renal failure.
RecommendationsParacetamol and/or a NSAID are effective for treating mild pain [I, A].
Paracetamol and/or a NSAID are effective for treating all intensities of
pain, at least in the short term and unless contraindicated [I, A].
Treatment of mild–moderate painIn the meta-analysis of Grond et
al. [39] on the analgesic efficacy and tolerability of weak opioids
versus placebo 10/16 RCTs show the superiority of opioids. However,
14/16 RCTs were single dose studies and no data are available on
longterm use.
Recently, tramadol at doses of 1 and 1.5 mg/kg every 6 h was compared
with placebo in 36 patients with neuropathic pain (NP) [40]. In the 18
patients on tramadol, significant improvements in pain relief, Karnofsky
Performance Status and sleep, as well as much more frequent adverse
effects such as nausea, vomiting and constipation were found.
In an RCT [41], the analgesia and tolerability of two doses of
hydrocodone/paracetamol (25 or 50/2500 mg/day) were compared with two
doses of tramadol (200 or 400 mg/day) in 118 patients. The PI reduction
was evident after the double dose intake, but a significant difference
in analgesia was not found. Moreover, the patients treated with tramadol
had a significant major incidence of nausea, vomiting, vertigo,
anorexia and asthenia.
In an RCT, the efficacy and tolerability of oral tramadol versus
hydrocodone and versus codeine was compared in 177 patients [42]. No
significant difference in analgesic efficacy was found; however the use
of tramadol produced a significantly higher percentage of side effects.
Traditionally [21], patients with mild–moderate pain have been treated
with a combination product containing acetaminophen, aspirin or NSAID
plus a weak immediaterelease opioid such as codeine, dihydrocodeine,
tramadol orpropoxyphene.
The use of drugs of the second step of the WHO ladder has several
controversial aspects. The first criticism concerns the absence of a
definitive proof of efficacy of weak opioids: in a meta-analysis of data
reported from clinical randomized controlled trials [43], no
significant difference was found in the effectiveness between nonopioid
analgesics alone, and the combination of these with weak opioids. The
available studies do not demonstrate a clear difference in the
effectiveness of the drugs between the first and the second step [44].
Uncontrolled studies also show that the effectiveness of the second step
of the WHO ladder has a time limit of 30–40 days for most patients and
that the shift to the third step is mainly due to insufficient analgesia
achieved, rather than to adverse effects [45]. A further limitation in
the use of weak opioids isrepresented by the ‘ceiling effect’, for which
more than a certain threshold of dose cannot increase the effectiveness
of the drug, but only influence the appearance of side effects. Many
authors have proposed the abolition of the second step of the WHO
analgesic ladder, in favor of the early use of morphine at low doses.
The few studies on this specific topic [46–48], thoughsuggestive, have
reported inconclusive results due both to the low number and
representativeness of the patient sample studied and to the relatively
low statistical power.
An RCT is strongly needed to address the relevant issue of the role of
WHO step II because data supporting the role of the modified two-step
analgesic ladder or oral tramadol as an alternative to
codeine/paracetamol are insufficient to recommend their routine use in
cancer patients with mild tomoderate cancer pain [49].
RecommendationsFor mild to moderate pain, weak opioids such as
codeine, tramadol and dihydrocodeine should be given in combination with
non opioid analgesics [III, C].
As an alternative to weak opiods, low doses of strong opiods in
combination with nonopiod analgesics should be considered [III, C].
Treatment of moderate–severe painStrong opioids are the
mainstay of analgesic therapy in treating moderate–severe cancer-related
pain. In some countries, pain relief is hampered by lack of
availability of, or barriers to accessibility to, opioid analgesics
[50]. Morphine, methadone, oxycodone, hydromorphone, fentanyl,
alfentanyl,buprenorphine, heroin, levorphanol, oxymorphone are the most
used strong opioids in Europe [50, 51]. In recent years, in some
countries, the consumption of oxycontin and patches of fentanyl and
buprenorphine has been increasing [52]. However, there is no evidence
from high-quality comparative studies that other opioids are superior to
morphine in terms ofefficacy and tolerability. New opioid analgesics
are now available, e.g. oxycodone/naloxone combination, which have been
shown to be effective and potentially have fewer side effects in some
clinical settings although further research into their clinical effects
in cancer patients is needed.
In many countries, since 1977, oral morphine has been used in hospices
and palliative care units as the drug of choice for the management of
chronic cancer pain of moderate to severe intensity because it provides
effective pain relief, is widely tolerated, simple to administer and
inexpensive. Moreover,morphine is the only opioid analgesic considered
in the WHO essential drug list for adults and children with pain [53].
RecommendationThe opioid of first choice for moderate to severe
cancer pain is oral morphine [IV, D]. Although the oral route of
administration is advocated, patients presenting with severe pain that
needs urgent relief should be treated and titrated with parenteral
opioids, usually administered by the subcutaneous (s.c.) or intravenous
(i.v.) route.
If given parenterally, the equivalent dose is one-third of the oral
medication. The relative potency ratio of oral to parenteral
(subcutaneous or intravenous) morphine (not subject to ‘first pass’
metabolism) [54, 55] might vary according to the circumstances in which
morphine is used and amongindividual patients. When converting from oral
to parenteral morphine, the dose should be divided by two or three to
get a roughly equianalgesic effect, but upward or downward adjustment of
the dose may then be required [56].
RecommendationsThe average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3 [II, A].
The average relative potency ratio of oral to subcutaneous morphine is between 1:2 and 1:3 [IV, C].
Hydromorphone or oxycodone, in both immediate-release and
modified-release formulations for oral administration and oral methadone
[51] are effective alternatives to oral morphine.
Transdermal fentanyl and transdermal buprenorphine are best reserved for
patients whose opioid requirements are stable. They are usually the
treatment of choice for patients who are unable to swallow, those with
poor tolerance of morphine and patients with poor compliance. Although
not recommended in the NCCN Clinical Practice Guidelines in Oncology for
AdultCancer Pain [22] because it is a partial agonist, buprenorphine
has a role in the analgesic therapy of patients with renal impairment
and undergoing hemodialysis treatment [57, 58] where no drug reduction
is necessary, with buprenorphine being mainly extracted through the
liver to norbuprenorphine(a metabolite 40 time less potent than the
parent compound). Methadone is a valid alternative but, because of
marked interindividual differences in its plasma half-life and duration
of action, it is still considered as a drug which should be initiated by
physicians with experience and expertise in its use [51]. Strong
opioids may be combined with ongoing use of a non opioid analgesic (step
1).
RecommendationsIn the presence of renal impairment, all opioids should be used with caution and at reduced doses and frequency [IV, C].
Fentanyl and buprenorphine via the transdermal route or intravenously
are the safest opioids of choice in patients with chronic kidney disease
stages 4 or 5 (estimated glomerular filtration rate <30 ml/min) [IV,
C].
Opiod switching is a practice used to improve pain relief and/or drug
tolerability. The most frequent switch is from morphine, oxycodone,
hydromorphone, fentanyl to oral methadone [51, 59, 60]. There is no
high-quality evidence to support this practice; however, a switch to an
alternative opioid is frequently used in clinical practice [61]. This
approachrequires familiarity with equianalgesic doses of the different
opioids [62].
Scheduling and titrationOpioid doses should be titrated to take
effect as rapidly as possible. Titration is a process in which the dose
of the opioid is speedily modified to obtain the tailored dose which
provides adequate relief of pain with an acceptable degree of side
effects. Normal-release morphine has a short half-life and is
indicated:during the titration phase; for treating BTP episodes; and for
treating predictable episodes of acute pain in patients on regular
analgesics (administration should take place 20-30 minutes before the
predictable episode of acute pain). Intravenous titration is indicated
in patients with severe pain (table 3) [63].
All patients should receive round-the-clock dosing with provision of a
‘rescue dose’ to manage transient exacerbations of pain. The
‘breakthrough dose’ is usually equivalent to +10% to 15% of the total
daily dose. If more than four ‘rescue doses’ per day are necessary, the
baseline opioid treatment with a slow-release formulation has to be
adapted. Opioids with a rapid onset and short duration are preferred as
rescue medications. Following the titration period, slow-release opioids
are indicated. However, immediate release opioids have always to be
prescribed as a rescue medication.
RecommendationsIndividual titration of dosages by means of
normal release morphine administered every 4 h plus rescue doses (up to
hourly) for BTP are recommended in clinical practice [IV, C].
The regular dose of slow-release opioids can then be adjusted to take into account the total amount of rescue morphine [IV, C].
Management of opioid side effectsMany patients develop adverse
effects such as constipation, nausea/vomiting, urinary retention,
pruritus and central nervous system (CNS) toxicity (drowsiness,
cognitive impairment, confusion, hallucinations, myoclonic jerks and —
rarely — opioid-induced hyperalgesia/allodynia). Sometimes, thereduction
of the opioid dose may reduce the incidence and/or severity of adverse
events. This may be achieved by using a coanalgesic or an alternative
approach such as a nerve block or radiotherapy (RT). Other strategies
include the continued use of antiemetics for nausea, laxatives for
constipation, major tranquilizers for confusion and psychostimulants
fordrowsiness. However, since some of the side effects may be caused by
accumulation of toxic metabolites, switching to another opioid agonist
and/or another route may allow titration to adequate analgesia without
the same disabling effects. This is especially true for symptoms of CNS
toxicity such as opioid-induced hyperalgesia/allodynia and myoclonic
jerks [64]. Treatment of opioid-related CNS symptoms: there is little
evidence for the use of methylphenidate in the management of
opioid-induced sedation and cognitivedisturbance [65]. It is not
possible to recommend other individual drugs for the treatment of any
other central side effect. Dose reduction or opioid switching is a
potential effective way to manage delirium, hallucination, myoclonus and
hyperalgesia [65]. Treatment of opioid-related constipation: there is a
strong recommendation to routinely prescribe laxatives for prophylaxis
and management of opioidinduced constipation [66]. Methylnaltrexone
administered by subcutaneous injection should be used in the treatment
of opioid-related constipation resistant to traditional laxatives [66].
Naloxone is a short-acting opioid antagonist for i.v. use able to
reverse symptoms of accidental severe opioid overdose. The potential
clinical effects on constipation of new pharmacological developments
(e.g. oxycodone and naloxone) have been demonstrated by a recent
randomized, double-blind,study aimed to investigate the safety and
efficacy of oxycodone/naloxone association in subjects with moderate to
severe chronic cancer pain [67].
Metoclopramide and antidopaminergic drugs are the drugs most frequently
used for treatment of opioid-related nausea/vomiting with a weak grade
[68, 69].
RecommendationsLaxatives must be routinely prescribed for both
the prophylaxis and the management of opioid-induced constipation [I,
A]. Metoclopramide and antidopaminergic drugs should be recommended for
treatment of opioid-related nausea/vomiting [III, B].
Breakthrough painA systematic literature review shows that
there is no widely accepted definition, classification system or any
well validated assessment tools for cancer-related BTP [70] and the
setting of care [71]. These findings could explain why the prevalence is
reported with a wide range from 19% to 95% [71–73]. Of interest in the
study of Greco et al. [71] 110 centers recruited1801 cancer patients of
which 40.3% had BTP at baseline. A strong association has been found
with the type of recruiting centers, with oncological wards reporting a
lower proportion of patients with BTP (−30%) when compared with
palliative centers.
Available pharmacological treatment options include oral transmucosal,
buccal, oral immediate-release morphine sulfate (IRMS) or nasal,
subcutaneous or intravenous opioids; however few RCTs are available
[74–76]. Seven RCTs were found: 5 studies were placebo controlled
studies that evaluated oral transmucosal fentanyl citrate (OTFC),
intranasal fentanyl spray (INFS), fentanyl buccal tablet; one trial
compared OTFC versus oral morphine [77]; and one trial compared INFS
versus OTFC [78].
Recently, a fentanyl pectin nasal spray (FPNS) was developed to optimize
the absorption profile of fentanyl across the nasal mucosa. An RCT
trial showed that a dose of FPNS provides superior pain relief compared
with placebo with apain reduction after five minutes with further and
significant reductions after 10 min [76].
Davies et al. [79] studied the consistency of efficacy, tolerability and
patient acceptability of FPNS versus IRMS in 110 patients experiencing
one to four BTP episodes/day during background pain treatment with oral
morphine or equivalent opioids ≥60 mg/day. At baseline and during an
open dose titration phase (maximum 2 weeks) followed by a double blind,
double dummy treatment phase (from 3 to 21 days) and an end-of-treatment
phase (1 to 14 days after the last dose) the PI was evaluated by means
of the NRS, and pain relief was measured on a 5-point numeric scale (0 =
none, 4 = complete) and recorded in an e-diary at 5, 10, 15, 30, 45 and
60 min after dosing. Moreover, the patients rated the overall
satisfaction and satisfaction with speed of relief (30 and 60 min), and
reliability 60 min after the nasal spray using a 4-point scale (1 = not
satisfied; 4 = very satisfied). After the last treated BTP episode
patients rated the ease of use and convenience of the nasal spray.
The per-episode analysis showed statistically significant differences in
PI scores and in pain relief in favor of FPNS versus IRMS by 10 min
after administration (P<0.05). Overall acceptability scores were
significantly greater for FPNS than for IRMS at 30 (P < 0.01) and 60
(P < 0.05). Most of the patients were ‘satisfied/very satisfied’ with
the convenience (79.8%) and ease of use (77.2%) of FPNS. Nobody
reported significant nasal effects.
In a prospective, multicenter phase IV study [80] sublingual fentanyl
orally disintegrating tablet (sublingual fentanyl ODT) was studied in
181 patients. During the study, 3163 episodes of BTP were treated with a
mean dose of 401.4 mcg per episode. With respect to baseline, a
significant improvement ofmaximum BTP intensity was seen with sublingual
fentanyl ODT (P < 0.0001) within 5 min of administration in 67.7% of
episodes and a maximum effect within 30 min in 63% of episodes. Quality
of life assessed by means of the modified pain disability index and
emotional distress assessed by Hospital Anxiety and Depression Scale
(HADS) significantly improved during an observational period of 28 days.
The drug was well tolerated.
RecommendationsImmediate release formulation of opioids must be used to treat exacerbations of controlled background pain [I, A].
Immediate release oral morphine is appropriate to treat predictable
episodes of BTP (i.e. pain on moving, on swallowing, etc.) when
administered at least 20 min before such potential pain triggers [II,
A].
Intravenous opioids; buccal, sublingual and intranasal fentanyl drug
delivery have a shorter onset of analgesic activity in treating BTP
episodes in respect to oral morphine [I, A].
Bone painTreatment of bone pain should always take into
consideration the use of analgesic drugs according to Algorithm 1.
Moreover, RT, radioisotopes and targeted therapy given in association
with analgesics have an important role in bone pain management
(Algorithm 2).
RadiotherapyRT has specific and critical efficacy in providing
pain relief caused by bone metastases, present in about 75% of patients
with cancer-related disease, and metastatic spinal cord compression
(MSCC) [81]. Numerous randomized prospective trials show improvements in
pain relief in 60%–80% of patients after RT [82]. The American Society
for Radiation Oncology (ASTRO), reviewing randomized published trials on
RT for painful bone metastases, showed pain relief equivalence for
different regimens, including 10 × 3Gy, 6 × 4Gy, 5 × 4Gy and 8-Gy single
dose [82]. Although fractionated RT regimenshave been associated with
an 8% repeat treatment rate to the same anatomic site because of
recurrent pain versus 20% after 8-Gy single dose, this last approach
should be considered the regimen of choice for patients with painful
bone metastases because it optimizes patient and caregiver convenience.
So, considering the equivalence in outcome of various RTregimens, and
the feasibility of reirradiation when necessary, 8-Gy single dose is
recommended in the majority of patients with painful bone metastases.
More protracted fractionated regimens should be reserved for
well-selected patients on the basis of better-expected outcomes [82].
Stereotactic body radiosurgery has emerged as a new treatment option
which permits the administration of very high/radioablative
doses—typically in single fraction (10–16 Gy) or in hypofractionation (3
× 9 or 5 × 6–8 Gy)—to the tumor avoiding excessive doses to surrounding
critical normal tissues such as the vertebrae or the spinal cord [83].
RecommendationsAll patients with painful bone metastases should
be evaluated for external beam RT and the dose prescription should be
8-Gy single dose [I, A].
Higher doses and protracted fractionations can be reserved only for selected cases [II, B].
Stereotactic body radiosurgery should be used for fit patients enrolled in clinical trials [V, D].
Spinal cord compression requires urgent oncologic care [84]. Pain
accompanies MSCC in ∼95% of patients, and usually precedes the diagnosis
by days to months. Pain can be local (back or neck pain), radicular or
both. Patients with neurologic deficits have a poor prognosis, thus
early clinical and MRI diagnosis and prompt therapy are powerful
predictors of outcome in MSCC [85–87].
Steroids should be given immediately when the clinicalradiological
diagnosis of MSCC is obtained. Dexamethasone is the most frequently used
drug, with doses ranging from moderate (16 mg/day) to high (36–96
mg/day) eventuallypreceded by a bolus of 10–100 mg intravenously. The
steroids are usually tapered over 2 weeks. Although no study has been
published comparing high-dose to moderate dexamethasone dose, 16 mg/day
remains the more often used prescription [84].
MSCC can be treated with surgery followed by RT or RT alone. RT is the
first line treatment for the majority of patients with MSCC; it provides
back pain relief in 50%–58% of cases with an interesting rate of pain
disappearing (30%–35% of cases) [85]. The optimal RT schedule remains
unknown. Assuggested by many prospective [85] and two phase III clinical
trials [86, 87], hypofractionated RT regimen can be considered the
approach of choice, while more protracted RT regimens (e.g. 5 × 4, 10 × 3
Gy) can be used in selected MSCC patients with a long life expectancy.
On the basis of the published evidence, it can be concluded that surgery
should be considered for a carefully selected group of patients, i.e.
with single-level MSCC and neurological deficits. Other possible
indications for surgery include the necessity of stabilization,
vertebral body collapse causing bone impingement on the cord or nerve
root, compression recurring after RT and an unknown primary requiring
histological confirmation for diagnosis [85, 88].
Radioisotope treatment has also been investigated in a systematic review
[89]: the results showed only a small beneficial effect on pain control
in the short and medium term (1–6 months), with no modification of the
analgesics used. Few RCTs, involving small numbers, have shown that
isotopes can relieve bone pain in patients with breast cancer and lung
cancer, while they produced inconsistent results in patients with
hormone refractory prostate cancer [90, 91].
RecommendationsEarly diagnosis and prompt therapy are powerful
predictors of outcome in MSCC [I, A]. The majority of patients with MSCC
should receive RT alone and surgery should be reserved only for
selected cases [II, B].
Hypofractionated RT regimen can be considered the approach of choice [I,
A], while more protracted RT regimens can be used in selected MSCC
patients with a long life expectancy [III, B].
Dexamethasone should be prescribed in patients with MSCC [II, A] at a medium dose [III, B].
Radioisotope treatment can be evaluated in selected patients with multiple osteoblastic bone metastases [II, C].
Targeted therapy and bone painBisphosphonatesBisphosphonates
(BPs) form part of the standard therapy for hypercalcemia and the
prevention of skeletal-related events (SREs) in some cancers. There is
sufficient evidence supporting the analgesic efficacy of BPs in patients
with bone pain due to bone metastases from solid tumors and multiple
myeloma[92]. However, the prescription of BPs should not be considered
as an alternative to analgesic treatment and their administration should
be started after preventive dental measures [93, 94]. After the first
i.v. infusions of BP, pain can appear or its intensity increase, and the
use of analgesics such as paracetamol or a basal analgesic dose
increase is necessary.
RecommendationsBisphosphonates should be considered as part of
the therapeutic regimen for the treatment of patients with/without pain
due to metastatic bone disease [II, B].
Preventive dental measures are necessary before starting bisphosphonate administration [III, A].
DenosumabDenosumab, a targeted RANK ligand inhibitor, is a new
therapy for the prevention of SREs. Three prominent clinical trials were
conducted to establish the efficacy of denosumab [95–97]. In two of
three trials, denosumab was found to delay the time to first
skeletal-related event significantly more thanzoledronic acid in
patients with breast or castration-resistant prostate cancer with bone
metastasis. The third trial found denosumab to be non-inferior to
zoledronic acid in patients with metastases from solid tumors, excluding
breast and prostate solid tumors.
The integrated analysis of pain outcomes, presented only in the form of
an abstract [98], found a superiority of denosumab when compared with
zoledronic acid in delay time to moderate/severe pain occurrence and in
reducing analgesic use. The prescription of denosumab should be started
afterpreventive dental measures [99].
RecommendationsDenosumab should be considered as a valid
alternative to BPs for the treatment of patients with/without pain due
to metastatic bone disease from solid tumors [I, A].
The role of denosumab in delaying bone pain occurrence is promising but deserves further investigation [III, B].
Preventive dental measures are necessary before starting denosumab administration [III, A].
Neuropathic painAlthough NP is considered frequent in cancer
patients and difficult to manage, only a few studies on the prevalence
of NP are available. A 1-month follow-up prospective epidemiological
multicenter study was carried out to assess the prevalence of NP and to
evaluate its management in 46 oncological units inSpain during a mean
period of four weeks [100]. Of 8615 screened patients, 2567 (30%)
suffered from pain. From these, 33% had NP according to investigators
and only 19% were confirmed by DN4 ≥4. Sixty-nine percent of NP cases
were tumor related and up to 43% treatment related. In those
casesrelated to treatment, 79% were due to chemotherapy or biologic
therapy. At baseline, physicians prescribed opioids to 88% of patients
and oxycodone was most frequently used (74%) followed by fentanyl (46%),
morphine (22%), tramadol (38%); nonopioid analgesic treatment was
prescribed to 67% ofpatients with NSAIDs as the most frequently used
(71%); and co-adjuvants with gabapentin as the most frequently used
(52%). After 1 month, PI decrease was significant in patients with
metastases (P < 0.01). This is the first prospective study including a
large sample of cancer patients evaluating the prevalence and the
pharmacological treatment of NP.
NP, either caused by tumor infiltration or due to paraneoplastic or
treatment-induced polyneuropathy, may be adequately controlled by
opioids alone ± adjuvant drugs. Evidence from studies in patients
without cancer has beenreviewed as the pathological mechanism of NP
involved is believed to be the same. There is evidence from systematic
reviews [101, 102] that both tricyclic antidepressants [101] and
anticonvulsant drugs are effective in the management of NP [101, 103,
104] even if the number NNT (number needed to treat) for these drugs is
3–5. Two specific systematic reviews have been identified on the role of
anticonvulsant drugs in NP: one dealing with gabapentin in the
management of pain and the other dealing with variousanticonvulsants
[104].
In cancer patients with NP, non-opioid and opioid analgesics may be
combined with tricyclic antidepressant drugs or anticonvulsants
(Algorithm 3). The efficacy and tolerability of the therapy have to be
monitored over time. Steroids should be considered in the case of nerve
compression. There isevidence in adults that intravenous lidocaine and
its oral analogue mexiletine are more effective than placebo in
decreasing NP and can relieve pain in selected patients [105].
In a phase III randomized trial in 270 patients with bone metastasis
treated with 8 Gy in one versus 20 Gy in five fractions of RT for NP due
to bone metastases, the higher dose was more effective than the single
dose of 8 Gy used for uncomplicated bone metastasis [106].
RecommendationsPatients with NP should be treated with non opioid and opioid drugs [III, B].
Patients with NP should be given either a tricyclic antidepressant or a
anticonvulsant and subjected to side effects monitoring [I, A].
In patients with neropathic pain due to bone metastases RT at the dose of 20 Gy in five fractions should be considered [II, B].
Intensive management of refractory painAbout 10% of cancer
patients have pain which is difficult to manage with oral or parenteral
analgesic drugs. Interventional techniques such as nerve blocks and
intrathecal drug delivery (ITDD) (spinal or epidural) [107] may allow
those patients refractory to all conventional strategies and/or dose
limitinganalgesic-related side effects to reach pain control when used
as unique therapy or, more frequently, in combination with systemic
therapy.
Two prospective comparative trials between oral and spinal morphine,
have compared the analgesia and tolerability of morphine administered
orally or by epidural [108, 109]. An improvement in pain control as well
as in adverse effects was shown by switching from oral to epidural or
continuous subcutaneous infusion of morphine [108]. Of interest, K also
showed no significant benefits, either in efficacy or in adverse
effects, by administering morphine epidural compared with the
subcutaneous route. The authors concluded that the coadministration of
local anesthetic agents, alpha-2-adrenergic agonists or
N-methyl-D-aspartate (NMDA) antagonists maysignificantly improve the
quality of epidural analgesia as compared with the SC route [109].
Intrathecal drug deliverySpinal opioids work by binding to the
mu receptor in the substantia gelatinosa and can be administered
epidurally or intrathecally via percutaneous catheters, tunneled
catheters, or implantable programmable pumps (Algorithm 4). The spinal
route leads to decreased opioid consumption: if the opioid is delivered
via the epidural route, only 20%–40% of the systemic dose is required to
reach equianalgesia and if the intrathecal route is adopted, only 10%
of the systemic dose for equianalgesia is required. The intrathecal
route of opioid administration should be considered in patients
experiencing pain in various anatomic locations: head and neck, upper
and lower extremities, trunk. The fully implanted systems offer less
risk of infection and need lower maintenance than the percutaneous, but
the positioning is more complex [109]. These interventional strategies
are not appropriate in patients with infections, coagulopathy, or very
short life expectancy. Many authors [108–113] indicate the use of a
trial of intraspinal analgesia using a temporary epidural or spinal
catheter to determine efficacy and appropriate dose range before pump
implantation.
When compared with epidural drug delivery, ITDD presents fewer catheter
problems, smaller drugs dose requirement and less adverse effects. In
addition, it gives better pain control and decreased risk of infection.
Intrathecal administration has the advantage of being less affected by
the presence of extensive epidural metastasis and morphine, ziconotide
and baclofen are the drugs most used, sometimes with local
anesthetics(bupivacaine 0.125%–0.25%) [112, 114]. Limited evidence
supports the use of subanesthetic doses of ketamine, an NMDA antagonist,
in intractable pain.
ITTD or epidural administration of opioids may be useful in patients
with: (i) inadequate pain relief despite systemic opioid escalating
doses; (ii) non-effective response to switching the opioid or the route
of administration as well as when side effects increase because of dose
escalation; (iii) life-expectancy >6 months justifies the implantable
IT pump but only after atrial using a temporary epidural or spinal
catheter [115].
RecommendationIntraspinal techniques monitored by a skilled
team should be included as part of cancer pain management strategy, but
widespread use should be avoided [II, B].
Peripheral nerve blockPeripheral nerve blocks or plexus blocks
can be used when pain occurs in the field of one or more peripheral
nerves, or if pain is caused by complications such as pathological
fracture or vascular occlusion [116]. However, peripheral nerve blocks
as the principal pain treatment is very rare, and they are alwaysused
together with systemic analgesia according to a
multipharmacologicapproach as in postoperative pain treatment. The use
of neurolytic agents on peripheral nerves produces a significant
incidence of neuritis; so in patients with good prognosis, this can
result in symptoms more difficult to controlthan the original pain.
Neurolytic blockadeNeurolytic blocks should be limited to those
patients with short life expectancy because they usually produce a
block lasting 3–6 months. For the sympathetic system, neurolytic blocks
should be considered as adjuvants to decrease the use of oral and/or
parenteral analgesics because the visceral pain mechanisms are complex
and change with progression of the disease.
This technique is used for the superior hypogastric plexus block,
ganglion impar block, when pelvic pain or perineal pain of visceral
origin is present respectively, but above all for the celiac plexus
block, when visceral pain is due to pancreatic cancer.
Neurolysis of celiac plexusCeliac plexus block (CPB) is useful
when pain is of visceral etiology only and due to cancer in the upper
abdomen or pancreas; it leads to pain control and frequently to a
decrease in the total amount of systemic drugs and their side effects
[117].
The technique used to perform CPB (anterior or posterior approach;
amount and concentration of nerolytic agent and time) may affect the
results and the duration of the analgesic effect. One new way to perform
this kind of CPB is represented by echo-endoscope guidance, placed in
the stomach just belowthe cardia [118]. CPB should be performed in the
presence of visceral pain and only if the clinical condition of the
patient is not poor. Previous studies have suggested that when there is
evidence of disease outside the pancreas, such as celiac or portal
adenopathy, or both, the success rate of this blockdecreases
significantly [119].
RecommendationCPB appears to be safe and effective for the
reduction of pain in patients with pancreatic cancer, with a significant
advantage over standard analgesic therapy until 6 months [II, B].
End of life painRecent data suggest that 53%–70% of patients
with cancer-related pain require an alternative route for opioid
administration, months and hours before death [120]. On some occasions,
as patients are nearing death, pain is perceived to be ‘refractory’.
Pain is often accompanied by other symptoms such as dyspnea, agitation,
delirium and anxiety. A careful assessment of the total suffering is
mandatory to plan the appropriate therapeutic intervention. In deciding
that pain is refractory, the clinician must, after a meticulous
assessment of physical pain and total suffering, perceive that the
furtherapplication of standard interventions as described above is
either: (i) incapable of providing adequate relief, (ii) associated with
excessive and intolerable acute or chronic morbidity or (iii) unlikely
to provide relief, so that other interventional approaches may be
necessary to control pain caused byobstruction of hollow organs. In this
situation, sedation may be the only therapeutic option capable of
providing adequate relief. The justification of sedation in this setting
is that it is an appropriate and proportionate goal. However, before
administering sedative drugs, all the possible causes of‘suffering’ must
be carefully assessed and evaluated by means of a multidisciplinary
specialist approach which includes also psychiatric, psychological and
pastoral care personnel. Commonly used agents include opioids,
neuroleptics, benzodiazepines, barbiturates and propofol. Irrespective
of the agent or agents selected, administration initially requires dose
titration to achieve adequate relief, followed subsequently by provision
of ongoing therapy to ensure maintenance of effect. A continuous
assessment of the suffering of the patient should be performed during
the sedation process.
ConclusionsThe review of published data shows that only a few
RCTs have been performed in the setting of cancer patients with pain.
This is the major reason for which the level of evidence and the grade
of recommendation are not strong in many cases. Further well executed
studies on large samples of patients are needed in order to answer the
many scientific questions and tobe able to treat patients in the best
way.
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