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Pain management
symposium article
Annals of Oncology 23 (Supplement 10): x294–x301, 2012 doi:10.1093/annonc/mds360
Pain management C. I. Ripamonti* Supportive Care in Cancer Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy
symposium article
introduction Pain is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’ [1]. Pain is both a sensation (conscious awareness of a noxious stimulus) and an emotional experience (intense feelings of displeasure resulting in a pattern of reactive behaviour). The perception of the intensity of pain is dependent on the interactions between nociceptive and nonnociceptive impulses in ascending pathways, as well as the activation of descending pain-inhibitory systems. Cancer pain may be acute, chronic, and episodic. From a pathophysiological point of view, pain can be classified as nociceptive (somatic and visceral), neuropathic (central, peripheral, sympathetic) idiopathic, or psychogenic [2].
prevalence Pain prevalence ranges from 64% in patients with metastatic, advanced, or terminal phase disease, 59% in patients on anticancer treatment, and 33% in patients after curative treatment [3]. In the 18 studies reporting the pain severity, one-third of the patients rated their pain as moderate to severe [3]. No difference in pain prevalence was found between the patients during anticancer treatment and those in advanced or
*Correspondence to: Dr C. I. Ripamonti, M.D. Supportive Care in Cancer Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian n 1, 20133 Milano, Italy. Tel: +39-02-2390-3644-3383-3641; Fax: +39-02-23904847; E-mail: carla.ripamonti@ istitutotumori.mi.it
terminal phase of the disease. In patients on oncological treatments, the most frequent causes of pain are painful peripheral neuropathy, radiation-induced brachial plexopathy, chronic pelvic pain secondary to radiation, post-surgical pain [4]. Pain has a high prevalence in specific cancer types such as pancreatic (44%) and head and neck cancer (40%) [5]. Moreover, nearly half of the cancer patients were undertreated with a high variability across study designs and clinical settings. Recent studies conducted both in Italy and in Europe [6, 7] confirmed these data, showing that pain was present in all phases of cancer disease (early and metastatic) and was not adequately treated in a substantial percentage of patients, ranging from 56% to 82.3%. In prospective study [8], the adequacy of analgesic care of cancer patients was assessed by means of pain management index in 1802 valid cases of in- and outpatients with advanced/metastatic solid tumour enrolled in specifically devoted to cancer and/or pain management (oncology/pain /palliative centres or hospices). The study showed that patients were still classified as potentially under-treated in 25.3% of the cases (range 9.8%–55.3%). Contrary to the percentage of incidence of pain of haematological patients reported in the literature years ago (i.e. 5% with leukaemia and 38% with lymphoma), a substantial proportion of patients with haematological malignancies may suffer from pain not only in the last months of life (83%) [6, 9] but also at the time of diagnosis and during active therapies (67.3%) [9, 10]. According to the World Health Organization (WHO), the incidence of cancer was 12
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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 either in patients with solid and haematological malignancies. The proper and regular self-reporting assessment of pain is the first step for an effective and individualized treatment. Opioids are the mainstay of analgesic therapy and can be associated with non-opioids drugs such as paracetamol or non-steroidal anti-inflammatory drugs and to adjuvant drugs (for neuropathic pain and symptom control). The role and the utility of weak opioids (i.e. codeine, dihydrocodeine, tramadol) are a controversy point. Morphine has been placed by World Health Organization on its Essential Drug List. In the comparative study with other strong opioids (hydromorphone, oxycodone), there is no evidence to show superiority or inferiority with morphine as the first choice opioid. Oral methadone is a useful and safe alternative to morphine. Methadone presents the potential to control pain difficult to manage with other opioids. Although the oral route of opioid administration is considered the one of choice, intravenous, subcutaneous, rectal, transdermal, sublingual, intranasal, and spinal routes must be used in particular situation. Transdermal opioids such as fentanyl and buprenorphine are best reserved for patients whose opioid requirements are stable. Switching from one opioid to another can improve analgesia and tolerability. Key words: assessment, bone pain, cancer pain, neuropathic pain, prevalence, treatment
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Annals of Oncology
• Inform the patients about pain and pain management and •
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Figure 1. Validated and most frequently used pain assessment tools.
667 470 new cases in 2008 and based on the projections, it will be >15 million in 2020 [11]. These statistics suggest that cancer-related pain may be a major issue of health care systems worldwide.
•
pain assessment Pain is always a subjective sensation; it is what the patient says it is [1] and may be affected by emotional, social, and spiritual components; thus, it has been defined as ‘total pain’. Individualized pain management should take into account the onset, type, site, duration, intensity, and temporal patterns of the pain (from this, it is often possible to define the cause of the pain), concurrent medical conditions, and, above all, the subjective perception of the intensity of pain that is not proportional to the type or to the extension of the tissue damage but depends on the interaction of physical, cultural, and emotional factors. The assessment of pain is based on the expression of pain as reported by the patients referred to the previous 24 h or at the moment of the evaluation and includes pain at rest and pain on movement. The proper and regular self-reporting assessment of pain (intensity and outcomes) with the help of validated assessment tools is the first step for an effective and individualized treatment. The most frequently used standardized scales [12] are visual analogue scales, verbal rating scale (VRS), and the numerical rating scale (NRS; Figure 1). Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain. The assessment of all components of suffering such as psychosocial distress should be considered and evaluated.
treatment principles of pain management An effective pain-relieving therapy [13–17] must considering the following issues:
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A number of clinical studies have confirmed the effectiveness of this approach, in >90% of patients whatever the social cultural environment was [18].
pharmacological treatment According to the published guidelines [13–15], opioids are the mainstay of analgesic therapy and are classified according to their ability to control the mild to moderate pain (codeine, dihydrocodeine, tramadol, dextropropoxyphene; second step of the WHO analgesic ladder) and to control the moderate to severe pain (morphine, methadone, oxycodone, buprenorphine, hydromorphone, fentanyl, heroin, levorphanol, oxymorphone; third step of the WHO analgesic ladder). Opioid analgesics can be combined with non-opioid drugs such as paracetamol or with non-steroidal anti-inflammatory drugs (NSAIDs) [19] and with adjuvant drugs [20]. Nonopioid drugs are effective for treating mild pain. Paracetamol [19] and NSAIDs are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder at least in the short-term and unless contraindicated. The long-term use of NSAIDS or Cox-2 selective inhibitor has to be carefully monitored and reviewed periodically because
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encourage them to take an active role in their pain management. Prevent the onset of pain by means of the ‘by the clock’ administration, taking into account the half-life, bioavailability and the duration of action of the different drugs; thus, analgesics for chronic pain should be prescribed on a regular basis and not on ‘as required’ schedule. Prescribe a therapy which is simple to be administered and easy to be managed by the patient himself and his family, particularly 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 should be advocated as first choice. Prescribe a rescue dose of a short- or immediate-release medication (as required) other than the regular basal opioid therapy to manage episodic pain [also called breakthrough pain (BTP)]. The type of rescue opioid medication may be the same of the type of medication taken on regular intervals or may be different according to the drug availability and the efficacy and tolerability of the short release formulation. Tailor the dosage, the type and the route of drugs administered according to each patient’s needs. The dose of the analgesic drugs is influenced by the intensity of pain and has to be promptly adjusted to reach a balance between pain relief and side effects. The rescue doses taken by the patients are an appropriate measure of the daily titration of the regular doses. Consider an alternative route for opioid administration when the oral administration 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. Prevent and treat the possible opioid-related adverse effects such as nausea, vomiting, and constipation.
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may be used to titrate and retitrate the opioid dosage to achieve pain relief individually even on a day-by-day basis. Once an effective morphine dosage is achieved by using NRM, one may switch to a sustained-release oral preparation or to a transdermal opioid using a dosage conversion guidelines. For patients with severe pain is necessary to consider intravenous titration (dose finding) with morphine. Table 1 shows three different approaches [33–35]. Recently, systematic reviews of other strong opioids such as hydromorphone and oxycodone were published [36, 37]. Both drugs are analogues of morphine with similar pharmacodynamics properties [38] and can be considered as an alternative to morphine in the treatment of moderate to severe cancer pain; however, there is no evidence that demonstrated superiority or inferiority compared with morphine as the first choice opioid. Oral methadone is considered to be a useful alternative to oral morphine. Methadone is characterized by a large interindividual variation in pharmacokinetics and by rapid and extensive distribution phases (half-life of 2–3 h) followed by a slow elimination phase (beta half-life of 15–60 h) that may cause accumulation if doses are too large or the dosing intervals are too short over a long period of time. This is the main reason why attention is required when using this drug for the treatment of chronic cancer pain. However, respiratory depression has never been reported by the authors who studied methadone in cancer patients [38–42]. Methadone has the potential to control pain that does not respond to morphine or other opioids, because methadone shows incomplete crosstolerance with other mu-opioid receptor agonist analgesics. Moreover, there is the possibility of using it instead of other opioids such as morphine, when accumulation of active metabolite is the cause of side effects such as myoclonus, sedation, confusion, nausea, and vomiting. Methadone is a more potent opioid than believed. The dose ratio between methadone and morphine varies from 1:4 until 1:14 according to the dose of morphine previously administered. For this reason, caution is recommended when switching from any opioid to methadone particularly in patients who are tolerant to high doses of opioids [38–42]. Although the oral route of opioid administration (the one of choice) is effective in most situations, intravenous (i.v. or e.v.), subcutaneous (SC), rectal, transdermal (TTS), sublingual, intranasal, and spinal administration must be considered in particular situation (Table 2) [38]. Fentanyl citrate has a very high analgesic potency (∼75 times more than morphine), is skin compatible having a lowmolecular weight with good solubility and thus suitable for transdermal administration. Transdermal fentanyl offers the advantage of providing up to 3 days continuous administration of a potent opioid, avoiding the use of syringes and expensive drug-infusion pumps for the treatment of cancer pain. The use of transdermal fentanyl is not indicated in opioid-naive patients, during the opioid titration phase and to control BTP. When switching from one opioid to transdermal fentanyl, the patient has to continue taking 50% of previous opioid dose during the first 24 h [43]. There is some clinical and preclinical evidence showing that transdermal fentanyl produces less constipation when compared with morphine and other strong opioids [44].
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they can provoke severe gastrointestinal bleeding and renal insufficiency. Although the role of ‘strong’ opioids is universally recognized in the treatment of moderate to severe pain, there is no common agreement regarding the role and the utility of the second step of the WHO analgesic ladder (‘weak’ opioids for mild to moderate pain) [19, 21–23]. No substantial differences in pain relief between non-opioids alone and non-opioids plus weak opioids have been reported in a meta-analysis of data from published randomized controlled trials [23]. Different results were obtained by Moore et al. [24] in a systematic review of randomized controlled trials on analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in post-operative pain. They found that 60 mg codeine added to paracetamol produced worthwhile additional pain relief even in single oral doses. The role and the utility of the second step of the WHO analgesic ladder have been debated by various authors. Controversial points regarding the use of the second step are that (i) there are insufficient data regarding the effectiveness of the so-called ‘weak’ opioids; (ii) there are few studies showing a real advantage in their use compared with strong opioids; (iii) the second-step drugs are often marketed in combination with a non-opioid such as paracetamol, aspirin, or NSAID, and it is the latter component that limits the dose; and (iv) these drugs are often expensive in respect to their potential benefits (cost–benefit ratio) [25]. Moreover in routine clinical practice, the question that arises is ‘Is there any difference in pain control and/or tolerability using weak opioids in respect to low dose of strong opioids in managing mild–moderate pain?’ Unfortunately, not robust data are available to solve the question. In few studies with a small number of patients, low dose of oral morphine in respect to weak opioids was a reliable method of mild–moderate pain management in opioid-naïve advanced cancer patients [26, 27]. However, further research is necessary. Data supporting the role of modified two-step analgesic ladders or oral tramadol as an alternative to codeine/ paracetamol are insufficient to recommend their routine use in cancer patients with mild to moderate cancer pain [28]. Since 1977, oral morphine is used by 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 comparatively cheap. The WHO expert committee introduced morphine as a major pain-relieving drug and has strongly asserted the necessity of making it available all over the world. Morphine is considered the gold standard ‘step III’ opioid [13, 14] and was placed by WHO on its Essential Drug List. Ideally two types of formulations are required: normalrelease morphine (NRM; for dose titration) and sustained release (for maintenance treatment) [29–31]. Although, some clinicians indicate no differences in using sustained release or NRM when initiating oral strong opioids therapy for pain control [32], it is clinically suggested that the best approach is to tailor the dosage of the opioid to the needs of the individual patients, starting treatment with oral NRM, because its dosage can be modified very quickly (also every hour) according to the patient’s needs [29–31]. This strategy
Annals of Oncology
symposium article
Annals of Oncology Table 1. Intravenous titration (dose finding) with morphine for severe cancer pain Authors (ref.) Study design and patients population Radbruch et al. [33]
Harris et al. [35]
Results
Prospective study. Twenty-six i.v. PCA pump programmed Oral SR morphine q12 h; Mean pain intensity (NRS 0–100): dose on the basis of the inpatients with uncontrolled pain, on for 24 h: 1 mg bolus, • at entry: 67; previous i.v. step II opioids. lockout interval of 50 . • after 5 h: 22; requirements. Maximum dose of 12 mg/ i.v.–PO conversion 1:2. • at day 7: 17; h. • at day 14: 12. BKP treated with i.v. PCA until stable analgesia was reached. Mean morphine dosage (i.v. PCA) in the first 24 h: 32 mg (range 4–78). Mean daily morphine dosage (PO + i.v. PCA for BKP) at PCA termination (range 2–6 days): 139 mg (range 20–376). Mean morphine dosage (PO) at day 14: 154 mg (range 20–344). No substantial adverse events. Prospective study. Forty-five inpatients i.v. bolus (2 mg every 20 ) Mean pain intensity (NRS 0–10). Oral SR morphine; dose with severe (NRS ≥7) and prolonged At entry: 8.1. repeated until analgesia or on the basis of the pain. At entry, 30 patients were on After 9.70 : 3.0 with a mean i.v. adverse effects were previous i.v. step II opioids, 15 were on step III reported. requirements. morphine dosage of 8.5 mg. opioids. i.v.–PO conversion: 1:3 Mean daily oral morphine dosage at for lower i.v. dosages, time to discharge: 131 mg (107–156) 1:2 for higher i.v. + 10.8 mg (i.v. extra doses). dosages. No substantial adverse events. The same i.v. dose was maintained for BKP in the first 24 h. Percentage of patients achieving i.v. group: i.v. group: RCT. satisfactory pain relief: 1.5 mg bolus every 100 Oral IR morphine q4 Sixty-two strong opioid-naïve h, on the basis of the patients. until pain relief (or • after 1 h: i.v. group, 84%; oral group, previous i.v. Pain intensity NRS ≥5. adverse effects). 25% (P < 0.001); requirements. Patients were randomized to receive Oral group: • after 12 h: i.v. group 97%; oral group i.v.: PO conversion 1:1. i.v. morphine (n = 31) or oral IR IR morphine 5 mg every 76% (P < 0.001); Rescue dose: the same morphine (n = 31). 4 h in opioids-naive • after 24 h: i.v. group and oral group dose every 1 h patients. similar. maximum. 10 mg in patients on Oral group: follow the weak opioids. Rescue same scheme. dose: the same dose every 1 h maximum. i.v. group: median morphine dosage (i.v.) to achieve pain relief: 4.5 mg (range 1.5–34.5). In the same group, mean morphine dosage (PO) after stabilization: 8.3 (range 2.5–30) mg. Oral group: median morphine dosage to achieve pain relief: 7.2 (2.5–15) mg. No substantial adverse events.
i.v., intravenous; PCA, patient-controlled analgesia; SR, slow release; IR, immediate release; NRS, numerical rating scale; step II of the WHO analgesic ladder; BKP, breakthrough pain.
Transdermal fentanyl and transdermal buprenorphine are not indicated during the titration period and are best reserved for patients whose opioid requirements are stable. They are an alterative treatment of choice to
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subcuntaneous and intravenous continuous infusion of opioids for patients who are unable to swallow, patients with poor tolerance of morphine, and patients with poor compliance. Moreover, buprenorphine has a role for
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Mercadante et al. [34]
Initial morphine dosage and Following dosage and route route
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Annals of Oncology
Table 2. Potential applications of the different routes of opioid administration Oral
Sublingual buccal
Rectal
CSI
Intravenous
Transdermala
Spinal
Vomiting Bowel obstruction Dysphagia Cognitive failure Diarrhoea Haemorrhoids Anal fissures Coagulation Disorders Severe Immunosuppression Generalized oedema Frequent dose changes Titration Breakthrough pain
− − − − −
++ ++ ++ − ++
++ ++ ++ − −
++ ++ ++ ++ ++
++ ++ ++ ++ ++
++ ++ ++ ++ ++
++ ++ ++ − ++
++
++
−
++
++
++
++
++
++
++
−
++
++
−
++ ++ ++a ++ ++b
++ ++ ++ ++ ++
++ ++ − + ++
− − ++# ++# ++#
++ ++ ++# ++# ++#
++ − − − −
− ++ + − −
+, may be indicated; ++, is indicated; −, is contraindicated. Fentanyl. b Only immediate-release formulations, # = patient-controlled analgesia, PCA. CSI, continuous subcutaneous infusion. a
Table 3. Conversion tables between different opioids (A) Conversion fentanyl / morphine
(B) Conversion fentanyl TTS-methadone
Oral release morphine 24 h
Parenteral morphine (Ev o Sc) 24 h
Fentanyl TTS*
Fentanyl TTS
Oral methadone
60 mg 90 mg 120 mg 180 mg
20 mg 30 mg 40 mg 60 mg
25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h
25 mcg/h = 0.6 mg 50 mcg/h = 1.2 mg 75 mcg/h = 1.8 mg 100 mcg/h = 2.4 mg
X 20 = 12 mg methadone/day X 20 = 24 mg methadone/day X 20 = 36 mg methadone/day X 20 = 48 mg methadone/day
(C) OTFC -oral morphine • OTFC 200 µ ∼ 60 mg oral morphine • OTFC 400 µ ∼ 120 mg oral morphine • OTFC 600 µ ∼ 180 mg oral morphine • OTFC 800 µ ∼ 240 mg oral morphine
(D) Conversion morphine - methadone Slow release oral morphine 24 hours or Equivalent Parenteral morphine 30–90 mg ≥90–300 mg ≥300–600 mg ≥600 mg
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Dose ratio when: *Adverse effects §Pain under control 4:1 8:1 12:1 14:1
Dose ratio when: *uncontrolled pain **Tolerance
Dose ratio when: *Uncontrolled pain **Adverse effects
4:1 + 33% 8:1 + 33% 12:1 + 33% 14:1 + 33%
4:1 + 20% 8:1 + 20% 12:1 + 20% 14:1 + 20%
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Symptoms
Annals of Oncology
patients with renal impairments and undergoing haemodialysis treatment [15–44].
switching the opioid and/or the route of administration
neuropathic pain Although neuropathic pain (NP) is considered frequent in cancer patients and difficult to manage with opioids, only few studies on the prevalence of NP are available [20]. 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 in Spain during a mean period of 4 weeks [50]. At baseline, physicians prescribed opioids to 88% of patients and oxycodone was the most frequent used (74%) followed by fentanyl (46%), morphine (22%), tramadol (38%); non-opioid analgesic treatment to 67% of patients with NSAIDs as the most frequent (71%), and coadjuvants with gabapentin as the most frequent (52%). After 1 month, pain intensity decrease was similar among the different types of primary tumour, but it was substantial in patients with metastases (P < 0.01) versus patients with no metastases. The changes in pain intensity were significantly different (P < 0.05)
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among treatment groups, with oxycodone showing the largest reduction. The study is particularly interesting due to the high number of cancer patients on active oncological therapies screened for NP in oncological units.
pancreatic pain In patients with painful inoperable pancreatic cancer opioid analgesics and celiac plexus neurolysis are two therapeutic options for pain management. In a meta-analysis of studies on the endoscopic ultrasound-guided (EUS) celiac plexus neurolysis (CPN), the reduction of pain was observed in ∼80% of patients [51]. Wyse et al. [52] randomized 98 patients with confirmed assessable pancreatic adenocarcinoma diagnosed by the EUS-guided fine-needle aspiration cytology, to early EUSCPN or conventional pain management. The intensity of pain by a seven-point Likert scale, the opioid consumption (morphine equivalent) and the QoL scores were assessed at 1 and 3 months. Compared with conventional analgesic therapy administered alone, the difference in mean percent change in pain score was greater after 1 month and substantially (P = .01) greater at 3 months in patients treated with early EUS-CPN who had also a trend in reduction of analgesic drugs consumption.
breakthrough pain BTP is defined ‘a transitory flare of pain that occurs on a background of relatively well controlled baseline pain’ [53]. The typical BTP episodes are of moderate to severe intensity, rapid in onset (minutes), and relatively short in duration (median 30 min) [53]. A systematic literature review shows that there is not widely accepted definition, classification system or well validated assessment tools for cancer-related BTP [54], and the setting of care [55]. These findings could explain why the prevalence is reported with a wide range from 19% to 95% [55]. Available pharmacological treatment options include oral, transmucosal, buccal, oral immediate-release morphine sulphate (IRMS), or nasal opioids; however, few RCTs are available [56–58]. However, only seven RCTs that were founded, five studies were placebo-controlled studies that evaluated oral transmucosal fentanyl citrate (OTFC), intranasal fentanyl spray (INFS), fentanyl buccal tablet, one trial compared OTFC with IRMS [59], and one trial compared INFS with OTFC [60]. Recently, a fentanyl pectin nasal spray (FPNS) was developed to optimize the absorption profile of fentanyl across the nasal mucosa: A RCT trial showed that FPNS provides superior pain relief compared with placebo [58]. The effects on pain are present after only 5 min after a dose with further significative reductions from 10 min after a dose [58]. The same results were found by Davies et al. [61] who studied the consistency of efficacy, tolerability, and patient acceptability of FPNS versus IRMS in 110 patients experiencing one to four BTP episodes/ day during a background pain treatment with oral morphine or equivalent opioids ≥60 mg/day. A statistically significant differences in pain intensity scores and in pain relief in favour of FPNS versus IRMS by 10 min after the administration (P < 0.05) were found. Overall acceptability scores were
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In clinical practice, we can observe patients treated with oral morphine or another opioid who present with an imbalance between analgesia and side effects. In particular, some clinical situations may be present: (i) pain is controlled, but there are some intolerable adverse effects for the patient; (ii) pain is not adequately controlled and it is impossible to increase the opioid dose because of adverse effects; or (iii) pain is not adequately controlled notwithstanding the continuous increase of the opioid dose, which does not produce adverse effects. According the data of literature, different therapeutic strategies may prevent or treat adverse effects: (i) general measures (reduce the opioid dose, hydrate the patient, correct abnormal biochemistry if present, reduce the number of comedication); (ii) administration of drug to relief symptoms/ side effects caused by other medications (such as antiemetics, laxative etc.); (iii) administration of the opioids by an alternative route; (iv) administration of an alternative opioid; or (v) switching to both an alternative opioid and route [38, 41, 45–49]. Data are not available to allow us to compare the advantages and disadvantages of the different therapeutic strategies such as the use of drugs to relieve the symptom(s), the switching of opioid, and/or the route of administration. Patients who have poor analgesic efficacy or tolerability with one opioid will frequently tolerate another opioid well, although the mechanisms that underlie this variability in the response to different opioids are not known. The selection of an alternative opioid is largely empirical. A pure opioid agonist such as oxycodone, methadone, hydromorphone, and fentanyl is recommended when morphine fails. Positive results in symptom control and pain relief were also obtained by switching the route of opioid administration. Dose ratio between different opioids has to be considered when opioid switching is performed (Table 3) [38, 41, 45–49].
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conclusions Physical pain is only one potential cause of suffering; thus, successful pain control requires attention to some or all of the other aspects of care and suffering, and this requires a multidisciplinary approach to treatment; failure to do this frequently results in unrelieved pain. Successful pain management requires treatment of the patient’s total pain: physical, psychological, social, spiritual, and cultural starting from the diagnosis and through the illness [63]. All the physicians are involved in the assessment and treatment of cancer-related pain, because this symptom can be treated in each setting of care [64, 65]. Each patient has his/her own threshold of pain. Adequate sleep, elevation of mood, diversion, empathy, and understanding all can raise an individual’s pain threshold. Alternatively, fatigue, anxiety, fear, anger, sadness, depression, and isolation can lower the pain threshold.
disclosure The author has declared no conflicts of interest.
references 1. International Association for the Study of Pain (IASP). Subcommittee on taxonomy. Classification of chronic pain. Descriptors of chronic pain syndromes and definition of pain terms. Pain 1986; 3 (suppl): S1–S225. 2. Koh M, Portenoy RK. Cancer pain syndromes. In Bruera ED, Portenoy RK (eds), Cancer pain. assessment and management. Cambridge, UK: Cambridge University Press 2010; 53–85. 3. Van den Beuken-van Everdingen MHJ, De Rijke JM, Kessels AG et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 1437–1449. 4. Sun V, Borneman T, Piper B et al. Barriers to pain assessment and management in cancer survivorship. J Cancer Surviv 2008; 2: 65–71. 5. Burton AW, Fanciullo GJ, Beasley RD et al. Chronic pain in cancer survivor: a new frontier. Pain Med 2007; 8: 189–198. 6. Costantini M, Ripamonti C, Beccaro M et al. Prevalence, distress, management and relief of pain during the last three months of cancer patients’ life. Results of an Italian mortality follow-back survey. Ann Oncol 2009; 20: 729–735.
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7. Breivik H, Cherny N, Collett F et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009; 20: 1420–1433. 8. Apolone G, Corli O, Caraceni A et al. Pattern and quality of care of cancer pain management. Results from the cancer pain outcome research study group. Br J Cancer 2009; 100: 1566–1574. 9. Bandieri E, Sichetti D, Luppi M et al. Is pain in haematological malignancies under-recognised? The results from Italian ECAD-O survey. Leukemia Res 2010; 34: e334–e335. 10. Morselli M, Bandieri E, Zanin R et al. Pain and emotional distress in leukemia patients at diagnosis. Leukemia Res 2010; 34: e67–e68. 11. Frankish H. 15 million new cancer cases per year by 2020, says WHO. The Lancet 2003; 361: 1278. 12. Caraceni A, Cherny N, Fainsinger R et al. The Steering Committee of the EAPC Research Network. Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European Association of Palliative Care. J Pain Symptom Manage 2002; 23: 239–255. 13. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization 1986. 14. World Health Organization. Cancer Pain Relief, 2nd edition. Geneva: World Health Organization 1996. 15. Ripamonti C, Bandieri E, Roila F, on behalf of the ESMO Guidelines Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22(Suppl 6): 69–77. 16. Paice JA, Ferrell B. The management of cancer pain. CA Cancer J Clin 2011; 61: 157–182. 17. Vignaroli E, Bennett MI, Nekolaichuk C et al. Strategic pain management: the identification and development of the International Association for Hospice and Palliative Care (IAHPC) Opioid Essential prescription package. J Palliative Med 2012; 15(2): 186–191. 18. Ripamonti C, Bandieri E. Cancer pain. Crit Rev Oncol Hematol 2009; 70: 145–149. 19. McNicol E, Strassels S, Gouds L et al. NSAIDs or paracetamol, alone or combined with opioids, for cancer pain (Cochrane Review). In the Cochrane Library Issue 1, 2006. Chichester: John Wyley. 20. Bennett NI. Effectiveness of antiepilectic or antidepressant drugs when added to opioids for cancer pain: systematic review. Palliat Med 2011; 25: 553–559. 21. Carlson RW, Borrison RA, Sher HB et al. A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac, tromethamine, acetaminophen plus codeine, and placebo in cancer pain. Pharmacotherapy 1990; 10: 211–216. 22. Strobel VE. Drug therapy in severe tumor pain: comparative study of a new combination preparation versus diclofenac-Na. Fortsch Med 1992; 110: 411–414. 23. Eisenberg E, Berkey C, Carr DB et al. Efficacy and safety of nonsteroidal anti-inflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994; 12: 2756–2765. 24. Moore A, Collins S, Carroll D et al. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain 1997; 70: 193–201. 25. Freynhagen R, Zenz M, Strumpf M. WHO step II: clinical reality or a didactic instrument? Der Schmerz 1994; 8: 210–215. 26. Mercadante S, Porzio G, Ferrera P et al. Low morphine doses in opioid-naive cancer patients with pain. J Pain Symptom Manage 2006; 31: 242–247. 27. Maltoni M, Scarpi E, Modenesi C et al. A validation study of the WHO analgesic ladder: a two-step vs three-step strategy. Support Care Cancer 2005; 13: 888–894. 28. Tassinari D, Drudi F, Rosati M et al. The second step of the analgesic ladder and oral tramadol in the treatment of mild to moderate cancer pain. A systematic review. Palliat Med 2011; 25(5): 410–423. 29. De Conno F, Ripamonti C, Fagnoni E et al. The MERITOStudy: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during ‘titration phase’ in patients with cancer pain. Palliat Med 2008; 22: 214–221. 30. Ripamonti C, Campa T, Fagnoni E et al. Normal release oral morphine starting dose in cancer patients with pain. Clin J Pain 2009; 25: 386–390.
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substantially greater for FPNS than for IRMS at 30 (P < 0.01) and 60 (P < 0.05), respectively. Most of the patients were ‘satisfied/very satisfied’ with the convenience (79.8%) and easy to use (77.2%) of FPNS. Nobody reported substantial nasal effects. In a prospective, multi-center phase IV study [62], sublingual fentanyl orally disintegrating tablet (ODT) was studied in 181 patients. During the study, 3163 episodes of BTP were treated with a mean dose of 401.4 μcg per episode. In respect to baseline, a substantial improvement of maximum BTP intensity appeared with sublingual fentanyl ODT (P < 0.0001) within 5 min of administration in 67.7% of episodes and 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 HADS substantially improved during the observational period of 28 days. The drug was well tolerated.
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50. Garcia de Paredes ML, del Moral Gonzalez F, Martinez del Prado P et al. First evidence of oncologic neuropathic pain prevalence after screening 8615 cancer patients. Results of the on study. Ann Oncol 2011; 22: 924–930. 51. Puli SR, Reddy JB, Bechtold ML et al. EUS-guided celiac plexus neurolysis for pain due to chronic pancreatitis or pancreatic cancer pain. A meta-analysis and systematic review. Dig Dis Sci 2009; 54: 2330–2337. 52. Wyse JM, Carone M, Paquin SC et al. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable cancer. J Clin Oncol 2011; 29: 3541–3546. 53. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 3: 273–281. 54. Haugen DF, Hjermstad MJ, Hagen N et al. Assessment and classification of cancer breakthrough pain: a systematic literature review. Pain 2010; 149(3): 476–482. 55. Greco MT, Corli O, Montanari M et al. Epidemiology and pattern of care of breakthrough cancer pain in a longitudinal sample of cancer patients. Results from the cancer pain outcome research and study group. Clin J Pain 2011; 27: 9–18. 56. Zeppetella G, Riberio MDC. Opioids for the management of breakthrough episodic pain in cancer patients. Cochrane Database Syst Rev 2006; 1: CDOO4311. 57. Vissers D, Stam W, Nolte T et al. Efficacy of intranasal fentanyl spray vs other opioids for breakthrough pain in cancer. Curr Med Res Opin 2010; 26: 1037–1045. 58. Portenoy RK, Burton AW, Gabrail N et al. the Fentanyl Pectin Nasal Spray 043 Study Group. A multicenter, placebo-controlled, double-blind, multiple-crossover study of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain. Pain 2010; 151: 617–624. 59. Coluzzi PH, Schwartzberg L, Conroy JD et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate OTFC and morphine sulphate immediate release MSIR. Pain 2001; 1–2: 123–130. 60. Mercadante S, Radbruch L, Davies AN et al. A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain- an open label, randomized, cross-over trial. Curr Med Res Opin 2009; 25(11): 2805–2815. 61. Davies A, Sitte T, Elsner F et al. Consistency of efficacy, patient accettability and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulphate in breakthrough cancer pain. J Pain Symptom Manage 2011; 41: 358–366. 62. Uberall MA, Muller-Schwefe Gerhard HH. Sublingual fentanyl orally disintegrating tablet in daily practice: efficacy, safety and tolerability in patients with breakthrough cancer pain. Curr Med Res Opin 2011; 27(7): 1385–1394. 63. Ripamonti C, Pessi MA, Boldini S. Supportive Care in Cancer Unit (SCCU) at the NCI of Milan: a New Integrated Model of Medicine in Oncology. Curr Opin Oncol 2012; 24: 391–396. 64. Sichetti D, Bandieri E, Romero M et al. for ECAD Working Group (file: ECAD working group .doc). Impact of setting of care on pain management in patients with cancer: a multicentre cross-sectional study. Ann Oncol 2010; 21: 2088–2093. 65. Ripamonti C, Santini D, Maranzano E et al. On Behalf of the ESMO Guideline Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23: 19 (Suppl 7): vii139–vii154.
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31. Hanks GW, De Conno F, Ripamonti C et al. Morphine in cancer pain: modes of administration. Expert Working Group of the European Association for Palliative Care. BMJ 1996; 312: 823–826. 32. Caraceni A, Hanks G, Kaasa S et al. Use of opioid analgesics in the treatment of cancer pain: evidenced-based recommendations from the EAPC. Lancet Oncol 2012; 13: e58–e68. 33. Radbruch L, Loick G, Schulzeck S et al. Intravenous titration with morphine for severe cancer pain: report of 28 cases. Clin J Pain 1999; 15(3): 173–178. 34. Mercadante S, Villari P, Ferrera P et al. Rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion. Cancer 2002; 95: 203–208. 35. Harris JT, Suresh Kumar K, Rajagopal MR. Intravenous morphine for rapid control of severe cancer pain. Palliat Med 2003; 17: 248–256. 36. King SJ, Reid C, Forbes K et al. A systematic review of oxycodone in the management of cancer pain. Palliat Med 2011; 25(5): 454–470. 37. Pigni A, Brunelli C, Caraceni A. The role of hydromorphone in cancer pain treatment: a systematic review. Palliat Med 2011; 25(5): 471–477. 38. Ripamonti C, Bareggi C. Pharmacology of opioid analgesia: clinical principles. In Bruera E, Portenoy R. (eds). Cancer pain. Assessment and management, Vol. 11. Cambridge, UK: Cambridge University Press 2010; 195–229. 39. Ventafridda V, Ripamonti C, Bianchi M et al. A randomized study on oral administration of morphine andmethadone in the treatment of cancer pain. J Pain Symptom Manage 1986; 1: 203–207. 40. Ripamonti C, Groff L, Brunelli C et al. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol 1998; 16: 3216–3221. 41. Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol Oncol Clin North Am 2002; 16: 543–555. 42. De Conno F, Groff L, Brunelli C et al. Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 1996; 14: 2836–2842. 43. US Food and DrugAdministration. FDA issues second safety warning on fentanyl skin patch [news release]. http://www.fda.gov/bbs/topics/NEWS/2007/ NEW01762.html. 44. Cachia E, Ahmedzai SH. Transdermal opioids for cancer pain. Curr Opin Support Palliat Care 2011; 5: 15–19. 45. Cherny N, Ripamonti C, Pereira J et al. Expert Working Group of the EAPC Network. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001; 19: 2542–2554. 46. Mercadante S, Casuccio A, Fulfaro F et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001; 19: 2898–2904. 47. Benitez-Rosario MA, Feria M, Salinas-Martin A et al. Opioid switching from transdermal fentanyl to oral methadone in patientswith cancer pain. Cancer 2004; 101: 2866–2873. 48. Mercadante S, Ferrera P, Villari P et al. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol 2005; 23: 5229–5234. 49. Burza M, Ginobbi P, Fusco G et al. Transdermal route as an alternative to oral administration of opioids in cancer pain. Clin Ter 1998; 14: 277–280.
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Pain management C. I. Ripamonti* Supportive Care in Cancer Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy
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introduction Pain is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’ [1]. Pain is both a sensation (conscious awareness of a noxious stimulus) and an emotional experience (intense feelings of displeasure resulting in a pattern of reactive behaviour). The perception of the intensity of pain is dependent on the interactions between nociceptive and nonnociceptive impulses in ascending pathways, as well as the activation of descending pain-inhibitory systems. Cancer pain may be acute, chronic, and episodic. From a pathophysiological point of view, pain can be classified as nociceptive (somatic and visceral), neuropathic (central, peripheral, sympathetic) idiopathic, or psychogenic [2].
prevalence Pain prevalence ranges from 64% in patients with metastatic, advanced, or terminal phase disease, 59% in patients on anticancer treatment, and 33% in patients after curative treatment [3]. In the 18 studies reporting the pain severity, one-third of the patients rated their pain as moderate to severe [3]. No difference in pain prevalence was found between the patients during anticancer treatment and those in advanced or
*Correspondence to: Dr C. I. Ripamonti, M.D. Supportive Care in Cancer Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian n 1, 20133 Milano, Italy. Tel: +39-02-2390-3644-3383-3641; Fax: +39-02-23904847; E-mail: carla.ripamonti@ istitutotumori.mi.it
terminal phase of the disease. In patients on oncological treatments, the most frequent causes of pain are painful peripheral neuropathy, radiation-induced brachial plexopathy, chronic pelvic pain secondary to radiation, post-surgical pain [4]. Pain has a high prevalence in specific cancer types such as pancreatic (44%) and head and neck cancer (40%) [5]. Moreover, nearly half of the cancer patients were undertreated with a high variability across study designs and clinical settings. Recent studies conducted both in Italy and in Europe [6, 7] confirmed these data, showing that pain was present in all phases of cancer disease (early and metastatic) and was not adequately treated in a substantial percentage of patients, ranging from 56% to 82.3%. In prospective study [8], the adequacy of analgesic care of cancer patients was assessed by means of pain management index in 1802 valid cases of in- and outpatients with advanced/metastatic solid tumour enrolled in specifically devoted to cancer and/or pain management (oncology/pain /palliative centres or hospices). The study showed that patients were still classified as potentially under-treated in 25.3% of the cases (range 9.8%–55.3%). Contrary to the percentage of incidence of pain of haematological patients reported in the literature years ago (i.e. 5% with leukaemia and 38% with lymphoma), a substantial proportion of patients with haematological malignancies may suffer from pain not only in the last months of life (83%) [6, 9] but also at the time of diagnosis and during active therapies (67.3%) [9, 10]. According to the World Health Organization (WHO), the incidence of cancer was 12
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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 either in patients with solid and haematological malignancies. The proper and regular self-reporting assessment of pain is the first step for an effective and individualized treatment. Opioids are the mainstay of analgesic therapy and can be associated with non-opioids drugs such as paracetamol or non-steroidal anti-inflammatory drugs and to adjuvant drugs (for neuropathic pain and symptom control). The role and the utility of weak opioids (i.e. codeine, dihydrocodeine, tramadol) are a controversy point. Morphine has been placed by World Health Organization on its Essential Drug List. In the comparative study with other strong opioids (hydromorphone, oxycodone), there is no evidence to show superiority or inferiority with morphine as the first choice opioid. Oral methadone is a useful and safe alternative to morphine. Methadone presents the potential to control pain difficult to manage with other opioids. Although the oral route of opioid administration is considered the one of choice, intravenous, subcutaneous, rectal, transdermal, sublingual, intranasal, and spinal routes must be used in particular situation. Transdermal opioids such as fentanyl and buprenorphine are best reserved for patients whose opioid requirements are stable. Switching from one opioid to another can improve analgesia and tolerability. Key words: assessment, bone pain, cancer pain, neuropathic pain, prevalence, treatment
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• Inform the patients about pain and pain management and •
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Figure 1. Validated and most frequently used pain assessment tools.
667 470 new cases in 2008 and based on the projections, it will be >15 million in 2020 [11]. These statistics suggest that cancer-related pain may be a major issue of health care systems worldwide.
•
pain assessment Pain is always a subjective sensation; it is what the patient says it is [1] and may be affected by emotional, social, and spiritual components; thus, it has been defined as ‘total pain’. Individualized pain management should take into account the onset, type, site, duration, intensity, and temporal patterns of the pain (from this, it is often possible to define the cause of the pain), concurrent medical conditions, and, above all, the subjective perception of the intensity of pain that is not proportional to the type or to the extension of the tissue damage but depends on the interaction of physical, cultural, and emotional factors. The assessment of pain is based on the expression of pain as reported by the patients referred to the previous 24 h or at the moment of the evaluation and includes pain at rest and pain on movement. The proper and regular self-reporting assessment of pain (intensity and outcomes) with the help of validated assessment tools is the first step for an effective and individualized treatment. The most frequently used standardized scales [12] are visual analogue scales, verbal rating scale (VRS), and the numerical rating scale (NRS; Figure 1). Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain. The assessment of all components of suffering such as psychosocial distress should be considered and evaluated.
treatment principles of pain management An effective pain-relieving therapy [13–17] must considering the following issues:
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•
A number of clinical studies have confirmed the effectiveness of this approach, in >90% of patients whatever the social cultural environment was [18].
pharmacological treatment According to the published guidelines [13–15], opioids are the mainstay of analgesic therapy and are classified according to their ability to control the mild to moderate pain (codeine, dihydrocodeine, tramadol, dextropropoxyphene; second step of the WHO analgesic ladder) and to control the moderate to severe pain (morphine, methadone, oxycodone, buprenorphine, hydromorphone, fentanyl, heroin, levorphanol, oxymorphone; third step of the WHO analgesic ladder). Opioid analgesics can be combined with non-opioid drugs such as paracetamol or with non-steroidal anti-inflammatory drugs (NSAIDs) [19] and with adjuvant drugs [20]. Nonopioid drugs are effective for treating mild pain. Paracetamol [19] and NSAIDs are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder at least in the short-term and unless contraindicated. The long-term use of NSAIDS or Cox-2 selective inhibitor has to be carefully monitored and reviewed periodically because
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•
encourage them to take an active role in their pain management. Prevent the onset of pain by means of the ‘by the clock’ administration, taking into account the half-life, bioavailability and the duration of action of the different drugs; thus, analgesics for chronic pain should be prescribed on a regular basis and not on ‘as required’ schedule. Prescribe a therapy which is simple to be administered and easy to be managed by the patient himself and his family, particularly 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 should be advocated as first choice. Prescribe a rescue dose of a short- or immediate-release medication (as required) other than the regular basal opioid therapy to manage episodic pain [also called breakthrough pain (BTP)]. The type of rescue opioid medication may be the same of the type of medication taken on regular intervals or may be different according to the drug availability and the efficacy and tolerability of the short release formulation. Tailor the dosage, the type and the route of drugs administered according to each patient’s needs. The dose of the analgesic drugs is influenced by the intensity of pain and has to be promptly adjusted to reach a balance between pain relief and side effects. The rescue doses taken by the patients are an appropriate measure of the daily titration of the regular doses. Consider an alternative route for opioid administration when the oral administration 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. Prevent and treat the possible opioid-related adverse effects such as nausea, vomiting, and constipation.
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may be used to titrate and retitrate the opioid dosage to achieve pain relief individually even on a day-by-day basis. Once an effective morphine dosage is achieved by using NRM, one may switch to a sustained-release oral preparation or to a transdermal opioid using a dosage conversion guidelines. For patients with severe pain is necessary to consider intravenous titration (dose finding) with morphine. Table 1 shows three different approaches [33–35]. Recently, systematic reviews of other strong opioids such as hydromorphone and oxycodone were published [36, 37]. Both drugs are analogues of morphine with similar pharmacodynamics properties [38] and can be considered as an alternative to morphine in the treatment of moderate to severe cancer pain; however, there is no evidence that demonstrated superiority or inferiority compared with morphine as the first choice opioid. Oral methadone is considered to be a useful alternative to oral morphine. Methadone is characterized by a large interindividual variation in pharmacokinetics and by rapid and extensive distribution phases (half-life of 2–3 h) followed by a slow elimination phase (beta half-life of 15–60 h) that may cause accumulation if doses are too large or the dosing intervals are too short over a long period of time. This is the main reason why attention is required when using this drug for the treatment of chronic cancer pain. However, respiratory depression has never been reported by the authors who studied methadone in cancer patients [38–42]. Methadone has the potential to control pain that does not respond to morphine or other opioids, because methadone shows incomplete crosstolerance with other mu-opioid receptor agonist analgesics. Moreover, there is the possibility of using it instead of other opioids such as morphine, when accumulation of active metabolite is the cause of side effects such as myoclonus, sedation, confusion, nausea, and vomiting. Methadone is a more potent opioid than believed. The dose ratio between methadone and morphine varies from 1:4 until 1:14 according to the dose of morphine previously administered. For this reason, caution is recommended when switching from any opioid to methadone particularly in patients who are tolerant to high doses of opioids [38–42]. Although the oral route of opioid administration (the one of choice) is effective in most situations, intravenous (i.v. or e.v.), subcutaneous (SC), rectal, transdermal (TTS), sublingual, intranasal, and spinal administration must be considered in particular situation (Table 2) [38]. Fentanyl citrate has a very high analgesic potency (∼75 times more than morphine), is skin compatible having a lowmolecular weight with good solubility and thus suitable for transdermal administration. Transdermal fentanyl offers the advantage of providing up to 3 days continuous administration of a potent opioid, avoiding the use of syringes and expensive drug-infusion pumps for the treatment of cancer pain. The use of transdermal fentanyl is not indicated in opioid-naive patients, during the opioid titration phase and to control BTP. When switching from one opioid to transdermal fentanyl, the patient has to continue taking 50% of previous opioid dose during the first 24 h [43]. There is some clinical and preclinical evidence showing that transdermal fentanyl produces less constipation when compared with morphine and other strong opioids [44].
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they can provoke severe gastrointestinal bleeding and renal insufficiency. Although the role of ‘strong’ opioids is universally recognized in the treatment of moderate to severe pain, there is no common agreement regarding the role and the utility of the second step of the WHO analgesic ladder (‘weak’ opioids for mild to moderate pain) [19, 21–23]. No substantial differences in pain relief between non-opioids alone and non-opioids plus weak opioids have been reported in a meta-analysis of data from published randomized controlled trials [23]. Different results were obtained by Moore et al. [24] in a systematic review of randomized controlled trials on analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in post-operative pain. They found that 60 mg codeine added to paracetamol produced worthwhile additional pain relief even in single oral doses. The role and the utility of the second step of the WHO analgesic ladder have been debated by various authors. Controversial points regarding the use of the second step are that (i) there are insufficient data regarding the effectiveness of the so-called ‘weak’ opioids; (ii) there are few studies showing a real advantage in their use compared with strong opioids; (iii) the second-step drugs are often marketed in combination with a non-opioid such as paracetamol, aspirin, or NSAID, and it is the latter component that limits the dose; and (iv) these drugs are often expensive in respect to their potential benefits (cost–benefit ratio) [25]. Moreover in routine clinical practice, the question that arises is ‘Is there any difference in pain control and/or tolerability using weak opioids in respect to low dose of strong opioids in managing mild–moderate pain?’ Unfortunately, not robust data are available to solve the question. In few studies with a small number of patients, low dose of oral morphine in respect to weak opioids was a reliable method of mild–moderate pain management in opioid-naïve advanced cancer patients [26, 27]. However, further research is necessary. Data supporting the role of modified two-step analgesic ladders or oral tramadol as an alternative to codeine/ paracetamol are insufficient to recommend their routine use in cancer patients with mild to moderate cancer pain [28]. Since 1977, oral morphine is used by 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 comparatively cheap. The WHO expert committee introduced morphine as a major pain-relieving drug and has strongly asserted the necessity of making it available all over the world. Morphine is considered the gold standard ‘step III’ opioid [13, 14] and was placed by WHO on its Essential Drug List. Ideally two types of formulations are required: normalrelease morphine (NRM; for dose titration) and sustained release (for maintenance treatment) [29–31]. Although, some clinicians indicate no differences in using sustained release or NRM when initiating oral strong opioids therapy for pain control [32], it is clinically suggested that the best approach is to tailor the dosage of the opioid to the needs of the individual patients, starting treatment with oral NRM, because its dosage can be modified very quickly (also every hour) according to the patient’s needs [29–31]. This strategy
Annals of Oncology
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Annals of Oncology Table 1. Intravenous titration (dose finding) with morphine for severe cancer pain Authors (ref.) Study design and patients population Radbruch et al. [33]
Harris et al. [35]
Results
Prospective study. Twenty-six i.v. PCA pump programmed Oral SR morphine q12 h; Mean pain intensity (NRS 0–100): dose on the basis of the inpatients with uncontrolled pain, on for 24 h: 1 mg bolus, • at entry: 67; previous i.v. step II opioids. lockout interval of 50 . • after 5 h: 22; requirements. Maximum dose of 12 mg/ i.v.–PO conversion 1:2. • at day 7: 17; h. • at day 14: 12. BKP treated with i.v. PCA until stable analgesia was reached. Mean morphine dosage (i.v. PCA) in the first 24 h: 32 mg (range 4–78). Mean daily morphine dosage (PO + i.v. PCA for BKP) at PCA termination (range 2–6 days): 139 mg (range 20–376). Mean morphine dosage (PO) at day 14: 154 mg (range 20–344). No substantial adverse events. Prospective study. Forty-five inpatients i.v. bolus (2 mg every 20 ) Mean pain intensity (NRS 0–10). Oral SR morphine; dose with severe (NRS ≥7) and prolonged At entry: 8.1. repeated until analgesia or on the basis of the pain. At entry, 30 patients were on After 9.70 : 3.0 with a mean i.v. adverse effects were previous i.v. step II opioids, 15 were on step III reported. requirements. morphine dosage of 8.5 mg. opioids. i.v.–PO conversion: 1:3 Mean daily oral morphine dosage at for lower i.v. dosages, time to discharge: 131 mg (107–156) 1:2 for higher i.v. + 10.8 mg (i.v. extra doses). dosages. No substantial adverse events. The same i.v. dose was maintained for BKP in the first 24 h. Percentage of patients achieving i.v. group: i.v. group: RCT. satisfactory pain relief: 1.5 mg bolus every 100 Oral IR morphine q4 Sixty-two strong opioid-naïve h, on the basis of the patients. until pain relief (or • after 1 h: i.v. group, 84%; oral group, previous i.v. Pain intensity NRS ≥5. adverse effects). 25% (P < 0.001); requirements. Patients were randomized to receive Oral group: • after 12 h: i.v. group 97%; oral group i.v.: PO conversion 1:1. i.v. morphine (n = 31) or oral IR IR morphine 5 mg every 76% (P < 0.001); Rescue dose: the same morphine (n = 31). 4 h in opioids-naive • after 24 h: i.v. group and oral group dose every 1 h patients. similar. maximum. 10 mg in patients on Oral group: follow the weak opioids. Rescue same scheme. dose: the same dose every 1 h maximum. i.v. group: median morphine dosage (i.v.) to achieve pain relief: 4.5 mg (range 1.5–34.5). In the same group, mean morphine dosage (PO) after stabilization: 8.3 (range 2.5–30) mg. Oral group: median morphine dosage to achieve pain relief: 7.2 (2.5–15) mg. No substantial adverse events.
i.v., intravenous; PCA, patient-controlled analgesia; SR, slow release; IR, immediate release; NRS, numerical rating scale; step II of the WHO analgesic ladder; BKP, breakthrough pain.
Transdermal fentanyl and transdermal buprenorphine are not indicated during the titration period and are best reserved for patients whose opioid requirements are stable. They are an alterative treatment of choice to
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subcuntaneous and intravenous continuous infusion of opioids for patients who are unable to swallow, patients with poor tolerance of morphine, and patients with poor compliance. Moreover, buprenorphine has a role for
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Mercadante et al. [34]
Initial morphine dosage and Following dosage and route route
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Table 2. Potential applications of the different routes of opioid administration Oral
Sublingual buccal
Rectal
CSI
Intravenous
Transdermala
Spinal
Vomiting Bowel obstruction Dysphagia Cognitive failure Diarrhoea Haemorrhoids Anal fissures Coagulation Disorders Severe Immunosuppression Generalized oedema Frequent dose changes Titration Breakthrough pain
− − − − −
++ ++ ++ − ++
++ ++ ++ − −
++ ++ ++ ++ ++
++ ++ ++ ++ ++
++ ++ ++ ++ ++
++ ++ ++ − ++
++
++
−
++
++
++
++
++
++
++
−
++
++
−
++ ++ ++a ++ ++b
++ ++ ++ ++ ++
++ ++ − + ++
− − ++# ++# ++#
++ ++ ++# ++# ++#
++ − − − −
− ++ + − −
+, may be indicated; ++, is indicated; −, is contraindicated. Fentanyl. b Only immediate-release formulations, # = patient-controlled analgesia, PCA. CSI, continuous subcutaneous infusion. a
Table 3. Conversion tables between different opioids (A) Conversion fentanyl / morphine
(B) Conversion fentanyl TTS-methadone
Oral release morphine 24 h
Parenteral morphine (Ev o Sc) 24 h
Fentanyl TTS*
Fentanyl TTS
Oral methadone
60 mg 90 mg 120 mg 180 mg
20 mg 30 mg 40 mg 60 mg
25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h
25 mcg/h = 0.6 mg 50 mcg/h = 1.2 mg 75 mcg/h = 1.8 mg 100 mcg/h = 2.4 mg
X 20 = 12 mg methadone/day X 20 = 24 mg methadone/day X 20 = 36 mg methadone/day X 20 = 48 mg methadone/day
(C) OTFC -oral morphine • OTFC 200 µ ∼ 60 mg oral morphine • OTFC 400 µ ∼ 120 mg oral morphine • OTFC 600 µ ∼ 180 mg oral morphine • OTFC 800 µ ∼ 240 mg oral morphine
(D) Conversion morphine - methadone Slow release oral morphine 24 hours or Equivalent Parenteral morphine 30–90 mg ≥90–300 mg ≥300–600 mg ≥600 mg
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Dose ratio when: *Adverse effects §Pain under control 4:1 8:1 12:1 14:1
Dose ratio when: *uncontrolled pain **Tolerance
Dose ratio when: *Uncontrolled pain **Adverse effects
4:1 + 33% 8:1 + 33% 12:1 + 33% 14:1 + 33%
4:1 + 20% 8:1 + 20% 12:1 + 20% 14:1 + 20%
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patients with renal impairments and undergoing haemodialysis treatment [15–44].
switching the opioid and/or the route of administration
neuropathic pain Although neuropathic pain (NP) is considered frequent in cancer patients and difficult to manage with opioids, only few studies on the prevalence of NP are available [20]. 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 in Spain during a mean period of 4 weeks [50]. At baseline, physicians prescribed opioids to 88% of patients and oxycodone was the most frequent used (74%) followed by fentanyl (46%), morphine (22%), tramadol (38%); non-opioid analgesic treatment to 67% of patients with NSAIDs as the most frequent (71%), and coadjuvants with gabapentin as the most frequent (52%). After 1 month, pain intensity decrease was similar among the different types of primary tumour, but it was substantial in patients with metastases (P < 0.01) versus patients with no metastases. The changes in pain intensity were significantly different (P < 0.05)
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among treatment groups, with oxycodone showing the largest reduction. The study is particularly interesting due to the high number of cancer patients on active oncological therapies screened for NP in oncological units.
pancreatic pain In patients with painful inoperable pancreatic cancer opioid analgesics and celiac plexus neurolysis are two therapeutic options for pain management. In a meta-analysis of studies on the endoscopic ultrasound-guided (EUS) celiac plexus neurolysis (CPN), the reduction of pain was observed in ∼80% of patients [51]. Wyse et al. [52] randomized 98 patients with confirmed assessable pancreatic adenocarcinoma diagnosed by the EUS-guided fine-needle aspiration cytology, to early EUSCPN or conventional pain management. The intensity of pain by a seven-point Likert scale, the opioid consumption (morphine equivalent) and the QoL scores were assessed at 1 and 3 months. Compared with conventional analgesic therapy administered alone, the difference in mean percent change in pain score was greater after 1 month and substantially (P = .01) greater at 3 months in patients treated with early EUS-CPN who had also a trend in reduction of analgesic drugs consumption.
breakthrough pain BTP is defined ‘a transitory flare of pain that occurs on a background of relatively well controlled baseline pain’ [53]. The typical BTP episodes are of moderate to severe intensity, rapid in onset (minutes), and relatively short in duration (median 30 min) [53]. A systematic literature review shows that there is not widely accepted definition, classification system or well validated assessment tools for cancer-related BTP [54], and the setting of care [55]. These findings could explain why the prevalence is reported with a wide range from 19% to 95% [55]. Available pharmacological treatment options include oral, transmucosal, buccal, oral immediate-release morphine sulphate (IRMS), or nasal opioids; however, few RCTs are available [56–58]. However, only seven RCTs that were founded, five studies were placebo-controlled studies that evaluated oral transmucosal fentanyl citrate (OTFC), intranasal fentanyl spray (INFS), fentanyl buccal tablet, one trial compared OTFC with IRMS [59], and one trial compared INFS with OTFC [60]. Recently, a fentanyl pectin nasal spray (FPNS) was developed to optimize the absorption profile of fentanyl across the nasal mucosa: A RCT trial showed that FPNS provides superior pain relief compared with placebo [58]. The effects on pain are present after only 5 min after a dose with further significative reductions from 10 min after a dose [58]. The same results were found by Davies et al. [61] who studied the consistency of efficacy, tolerability, and patient acceptability of FPNS versus IRMS in 110 patients experiencing one to four BTP episodes/ day during a background pain treatment with oral morphine or equivalent opioids ≥60 mg/day. A statistically significant differences in pain intensity scores and in pain relief in favour of FPNS versus IRMS by 10 min after the administration (P < 0.05) were found. Overall acceptability scores were
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In clinical practice, we can observe patients treated with oral morphine or another opioid who present with an imbalance between analgesia and side effects. In particular, some clinical situations may be present: (i) pain is controlled, but there are some intolerable adverse effects for the patient; (ii) pain is not adequately controlled and it is impossible to increase the opioid dose because of adverse effects; or (iii) pain is not adequately controlled notwithstanding the continuous increase of the opioid dose, which does not produce adverse effects. According the data of literature, different therapeutic strategies may prevent or treat adverse effects: (i) general measures (reduce the opioid dose, hydrate the patient, correct abnormal biochemistry if present, reduce the number of comedication); (ii) administration of drug to relief symptoms/ side effects caused by other medications (such as antiemetics, laxative etc.); (iii) administration of the opioids by an alternative route; (iv) administration of an alternative opioid; or (v) switching to both an alternative opioid and route [38, 41, 45–49]. Data are not available to allow us to compare the advantages and disadvantages of the different therapeutic strategies such as the use of drugs to relieve the symptom(s), the switching of opioid, and/or the route of administration. Patients who have poor analgesic efficacy or tolerability with one opioid will frequently tolerate another opioid well, although the mechanisms that underlie this variability in the response to different opioids are not known. The selection of an alternative opioid is largely empirical. A pure opioid agonist such as oxycodone, methadone, hydromorphone, and fentanyl is recommended when morphine fails. Positive results in symptom control and pain relief were also obtained by switching the route of opioid administration. Dose ratio between different opioids has to be considered when opioid switching is performed (Table 3) [38, 41, 45–49].
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conclusions Physical pain is only one potential cause of suffering; thus, successful pain control requires attention to some or all of the other aspects of care and suffering, and this requires a multidisciplinary approach to treatment; failure to do this frequently results in unrelieved pain. Successful pain management requires treatment of the patient’s total pain: physical, psychological, social, spiritual, and cultural starting from the diagnosis and through the illness [63]. All the physicians are involved in the assessment and treatment of cancer-related pain, because this symptom can be treated in each setting of care [64, 65]. Each patient has his/her own threshold of pain. Adequate sleep, elevation of mood, diversion, empathy, and understanding all can raise an individual’s pain threshold. Alternatively, fatigue, anxiety, fear, anger, sadness, depression, and isolation can lower the pain threshold.
disclosure The author has declared no conflicts of interest.
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substantially greater for FPNS than for IRMS at 30 (P < 0.01) and 60 (P < 0.05), respectively. Most of the patients were ‘satisfied/very satisfied’ with the convenience (79.8%) and easy to use (77.2%) of FPNS. Nobody reported substantial nasal effects. In a prospective, multi-center phase IV study [62], sublingual fentanyl orally disintegrating tablet (ODT) was studied in 181 patients. During the study, 3163 episodes of BTP were treated with a mean dose of 401.4 μcg per episode. In respect to baseline, a substantial improvement of maximum BTP intensity appeared with sublingual fentanyl ODT (P < 0.0001) within 5 min of administration in 67.7% of episodes and 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 HADS substantially improved during the observational period of 28 days. The drug was well tolerated.
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