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Pain Therapy

1. GENERAL INFORMATION

1.1 Introduction

Each year cancer-related pain afflicts approximately 9 million people worldwide (Bonica 1990). According to World Health Organization (WHO) projections, there will be 15 million new cases of cancer, accounting for 9 million deaths by 2021. These statistics suggest that cancer-related pain may be a major issue of healthcare systems worldwide. The incidence of pain considering all stages of the disease has been reported to be 51%, which can increase to 74% in the advanced and terminal stages (Daut 1982). For patients with advanced cancer, pain is moderate to severe in about 40-50% and very severe or excruciating in 25-30%. Most patients with advanced cancer have at least two types of cancer-related pain which derives from a variety of aetiologies (Hearn 2003; O’Mahony 2003). Sixty-nine percent of patients rate their worst pain at a level that impaired their ability to function (Larue 1995). According to the International Association for the Study of Pain (IASP), Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” (IASP 1979; IASP 1986). 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). Pain is always a subjective sensation; it is what the patient says it is (IASP 1979; IASP 1986) and may be affected by emotional, social and spiritual components (Quill 2000) thus it has been defined as “total pain”. The perception of the intensity of pain is not proportional to the type or to the extent of the tissue damage but is dependent on the interactions between nociceptive and non-nociceptive impulses in ascending pathways, as well as the activation of descending pain-inhibitory systems. Cancer pain may be acute, chronic, episodic, or intermittent (Bonica 1990) (Table 1). From a pathophysiological point of view, pain can be classified as nociceptive (somatic and visceral), neuropathic (central, peripheral, sympathetic) idiopathic or psychogenic (Patt 1993; Fields 1994). Table 2 shows the semantic descriptors of neuropathic pain according to the IASP (IASP 1986). In cancer patients, pain is a direct result of the tumour in 75-80% of cases, is caused by anticancer treatments in 15-19% of patients and is unrelated to cancer and its treatments in 3-5% (Foley 2004). This coincidental pain has a variety of causes, for example it may be related to debility, decubitus (nociceptive), or post-herpetic neuralgia (neuropathic-peripheral and central). Pain may also be a consequence of the diagnostic procedures used in cancer treatment. Numerous distinct acute and chronic cancer pain syndromes (Table 3) have been recognized and described (Foley 2004; Reddy 2006). A proper pain assessment is fundamental for an effective and individualised treatment. Poor pain assessment is the greatest barrier to effective cancer pain management (Von Roenn 1993). As pain is a subjective perception, objective measurement is not possible. A variety of instruments have been developed to measure the intensity of pain (Caraceni 2002). Table 4 shows the guidelines for a correct assessment of the patient with pain.

Table 1 TEMPORAL CLASSIFICATION OF PAIN

ACUTE PAIN follows injury to the body and generally disappears when the body injury heals. It is usually due to a definable nociceptive cause. It has a definite onset and its duration is limited and predictable. It is often associated with objective physical signs of autonomic nervous system activity. Acute pain may also indicate a progression of disease and is often accompanied by anxiety.
CHRONIC PAIN is due to the progression of the disease and is rarely accompanied by signs of sympathetic overactivity and the site and the intensity may vary over the time. Chronic pain may be accompanied by changes in personality, lifestyle, and functional abilities and by symptoms and signs of depression. Chronic pain with overlapping episodes of acute pain (i.e. breakthrough pain) is probably the most common pattern observed in patients with ongoing cancer pain. This indicates the necessity for intermittent changes in therapy. Furthermore, the appearance of acute pain, or progression of a previously stable chronic pain, is suggestive of a change in the underlying organic lesion and often requires clinical re-evaluation.
BREAKTHROUGH PAIN (EPISODIC PAIN) is defined as transient flares of severe or excruciating pain in patients already being managed with analgesics. It arises in 64% of cancer patients with a median duration of 30 minutes (range 1 to 240). The most frequent causes of breakthrough pain are as follows: an insufficient amount of opioids taken at regular intervals; incident pain due to the patient’s moving, swallowing, or coughing; bowel distension, exacerbation of the neuropathic pain, or the onset of some other pains. The usual therapeutic approach in treating breakthrough pain is the administration of an opioid rescue dose equivalent to 5% to 10% of the total daily opioid intake concurrently with the regularly scheduled drug.
INTERMITTENT PAIN is unpredictable in onset and duration. The administration of around-the-clock opioids is not sufficient to give analgesia during these painful episodes and sedation usually supervenes during pain-free intervals. Intermittent pain is usually best managed by the p.r.n. administration of an opioid of rapid onset and short duration.

Table 2 Semantic descriptors of neuropathic pain (IASP 1979; IASP 1986)

Allodynia: pain caused by a stimulus which normally does not provoke pain
Causalgia: continuous burning pain, allodynia and hyperpathia in succession or a traumatic nervous lesion; disturbed vasomotor functions are often intercurrent, as well as, later on, disturbances to trophism
Central pain: pain associated with a lesion of the central nervous system
Dysesthesia: unpleasant sensation of tingling, stabbing or burning whether spontaneous or provoked Hyperesthesia: increase in sensitivity to specific stimuli
Hyperalgesia: increased response to a stimulus which is normally painful
Hyperpathia: painful syndrome characterised by increased reaction to a stimulus, especially a repetitive stimulus
Paresthesia: abnormal sensation, either spontaneous or evoked.

Table 3 Chronic Pain syndromes in cancer patient
1. Pain due to direct involvement
A. Tumor invasion of bone:
Multifocal or generalized bone pain
Pain syndromes of the bony pelvis and hip
Base of skull metastases Vertebral body metastases
Orbital syndrome Atlantoaxial syndrome
Parasellar syndrome C7-T1 syndrome
Middle cranial fossa syndrome T12-L1 syndrome
Jugular foramen syndrome Sacral syndrome
Clivus syndrome
Sphenoid sinus syndrome
Cavernous sinus syndrome
Occipital condyle syndrome
Odontoid fracture and atlantoaxial destruction
Back pain and epidural spinal compression
B. Tumor Invasion of nerves: Peripheral nerve syndrome
Paraspinal mass Chest wall mass
Retroperitoneal mass Painful mononeuropathy
cervical, brachial, lumbar,
sacral plexopathies
Painful polyneuropathy
Painful radiculopath
Epidural spinal cord compression Leptomeningeal metastases
C. Tumor invasion of viscera
D. Tumor invasion of blood vessels
E. Tumor invasion of mucous membranes
2. Pain due to cancer therapy
Postoperative pain syndrome Postchemotherapy pain syndrome
Post- thoracotomy Mucositis
Steroid pseudorheumatism Chronic Peripheral neuropath
(toxic, paraneoplastic)
Post-mastectomy Aseptic necrosis of femoral or humeral head
Post-radical neck resection Plexopathy
Phantom Pain Syndromes
(limb, breast, anus, bladder pain)
Raynaud’s Phenomenon
Post-surgical pelvic floor myalgia
Stump pain
Post-operative frozen shoulder
Postradiation pain syndrome
Radiation mielopathy Mucositis
Radiation necrosis of bone Radiation-induced peripheral nerve tumors
Radiation fibrosis of brachial
or lumbosacral plexus
Radiation Enteritis and Proctitis
Burning Perineum Syndrome
Chronic pain associated with hormonal therapy
Gynecomastia with hormonal therapy for prostate cancer
3. Pain directly related or unrelated to cancer
Paraneoplastic syndrome
Myofascial pain syndrome
Postherpetic neuralgia
Debility, constipation, bed sores, rectal or bladder spasm, gastric distension
Osteoporosis

Table 4 GUIDELINES FOR A CORRECT ASSESSMENT OF THE PATIENT WITH PAIN

ASSESS and RE-ASSESS THE PAIN

  • the onset, type, site, duration, intensity, relief and temporal patterns of the pain
  • the presence of the trigger factors and the signs and symptoms associated with the pain
  • the use of analgesics and their efficacy and tolerability

ASSESS and RE-ASSESS THE PATIENT

    • -the clinical situation by means of a complete/specific physical examination and the specific radiological and/or biochemical investigations
    • the presence of interference of pain with the patient’s daily activities, work, social life, sleep patterns, appetite, sexual functioning and mood
    • the impact of the disease and the therapy on the physical, psychological and social conditions
    • the presence of a caregiver, the psychological status, the degree of awareness of the disease, anxiety and depression and suicidal ideation, his/her social enviroment, quality of life, spiritual concerns/needs
    • the presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes
    • the functional status
    • -the presence of opiophobia

ASSESS and RE-ASSESS YOUR ABILITY TO COMMUNICATE WITH THE PATIENT AND THE FAMILY

    • take time to spend with the patient and the family to understand their needs

2. TREATMENT

2.1 Analgesic treatment strategy

In 1986 the World Health Organisation (WHO) published analgesic guidelines for the treatment of cancer pain based on a three step ladder (WHO 1986) and practical recommendations (Box 1).These guidelines serve as an algorithm for a sequential pharmacological approach to treatment according to the intensity of pain as reported by the patient. Non-opioid drugs such as NSAIDs or paracetamol are suggested for pain of mild intensity moving on to opioids for more troublesome pain. Opioid analgesics are classified according to their ability to control mild to moderate pain (i.e., codeine, tramadol, dextropropoxyphene; dihydrocodeine) and those used for moderate to severe pain (morphine, methadone, oxycodone, buprenorphine, hydromorphone, fentanyl, diamorphine) (WHO 1996). Adjuvant drugs are a class of co-analgesics to administer in association with opioids is some pain syndromes. The WHO 3-step analgesic ladder remains the clinical model for pain therapy. Its clinical application should be employed only after a complete and comprehensive assessment and evaluation based on the needs of each patient. When applying the WHO guidelines, up to 90% of the patients can find relief from their pain regardless of the settings of care, social and/or cultural environment (Ventafridda 1987; Grond 1991; Zech 1995; Mercadante 1999; NCI 1990; EWGEAPC 1996; Hanks 2001; Jacox 1994). Such a pharmacological approach is the standard treatment for patients with cancer pain on a type C basis. Only when such an approach is ineffective are interventions such as spinal administration of opioid analgesics or neuroinvasive procedures recommended.

Box 1

An effective pain-relieving therapy must:

  • prevent the onset of pain: for this purpose drugs are not administered “as required” but rather “by the clock”, taking into account the half-life, bioavailability and duration of action of the different drugs;
  • be simple to administer, thus easy to manage for the patient himself and his family, especially when the patient is cared for at home. The oral route appears to be the most suitable to meet this requirement, and, if it is well tolerated, must be considered as the preferential route of administration;
  • be individualized: the dosage, the type and the route of drugs used must be administered according to each patient’s needs. Individualized pain management should take into account the stage of disease, concurrent medical conditions, characteristics of pain, and psychological and cultural status of the patient.

2.2 Treatment of mild pain

2.2.1 Non opioid drugs

Aspirin, paracetamol (acetaminophen) and the non-steroidal anti-inflammatory drugs (NSAIDs) given as single analgesic treatment constitute the first step of the WHO analgesic ladder and are recommended as the sole treatment of mild pain. They may also be combined with opioids for moderate to severe or for very severe pain. A meta-analysis of published randomised controlled trials (RCTs) showed that single-dose NSAIDs provide greater analgesic efficacy than placebo, and an there was an approximate equivalence to a 5 to 10 mg dose of intramuscular morphine (Eisenberg 1994) on a type 1 level of evidence. Paracetamol induces a central analgesic effect (Piletta 1991); it has proven as effective and potent as aspirin in single-dose studies in cancer pain (Beaver 1990). NSAIDs are commonly defined as ”peripheral” analgesics, although there is increasing evidence that they have a central or not exclusively prostaglandin-mediated action (Willer 1989; Fink 1982; Martini 1984; Zecca 1988). The ceiling dose limits the utility of the NSAIDs used alone for mild to moderate pain, but provide additive analgesia when combined with opioids in the treatment of more severe pain (Ferrer-Brechner 1984). The addition of NSAIDs and paracetamol to opioids causes a synergistic effect so that lower doses of opioids may now produce pain relief with fewer side effects (Beaver 1984; Bjorkman 1993; Weingart 1985). There are no conclusive studies showing which non-opioid is more effective in cancer pain, and neither the proper doses nor route of administration have been established in prospective trials. The great inter-individual variability in response to different drugs suggests that a favourable previous exposure to a particular agent is an indicator that the same drug will be effective again (Ventafridda 1990). In clinical practice the administration of NSAIDs alone for analgesic purposes is indicated only for periods of up to 3 to 5 weeks because of lack of efficacy as well as side effects which arise from the chronic use of full doses of such drugs (Ventafridda 1987; Ventafridda 1980).

2.2.2 Opioid analgesics

According to the WHO, opioid analgesics are the mainstay of therapy for cancer-related pain. Opioids are used in the management of mild to severe cancer pain. Opioids produce analgesia by means of the stereospecific interaction with receptors located in different parts of the CNS, at either the spinal or supra-spinal level, and outside the CNS.

2.3 Treatment of mild-moderate pain

The weak opioids most frequently used are codeine, dihydrocodeine, tramadol, and dextropropoxyphene (WHO step II). No significant 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 (Eisenberg 1994). Different results were obtained by Moore et al. (Moore 1997) in a systematic review of randomized controlled trials on the degree of analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain. They found that 60 mg codeine added to paracetamol produced worthwhile additional pain relief even in single oral doses. Uncontrolled studies show that the efficacy of the second step of the WHO ladder is limited in time to 30 to 40 days in the majority of patients and that switching to strong opioids is mainly due to poor analgesia rather than to adverse effects (Ventafridda 1987; De Conno 1991; Radbruch 1994; Mercadante 1992). In a study of 944 patients treated with drugs from the second step of the ladder, 24% of the patients still benefited after 1 month of treatment, but the percentage had decreased to 4% after 90 days (De Conno 1991). This study evaluated several drugs, including oxycodone at low doses and buprenorphine, which are now considered appropriate drugs for moderate to severe pain (WHO 1986). Unlike the role of “strong” opioids, which is universally recognized in the treatment of moderate to severe pain, there is no common agreement regarding the role of “weak” opioids for mild to moderate pain. Controversial points regarding the use of second step are that 1) there are insufficient data regarding the effectiveness of the so-called “weak” opioids; 2) there are few studies showing a real advantage in their use compared with strong opioids; 3) 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 4) these drugs are often expensive in respect to their potential benefits (cost-benefit ratio). The role and the utility of the second step of the WHO analgesic ladder has been debated by various authors. Several authors have suggested abolishing the second step and initiating earlier low-dose morphine therapy (Eisenberg 1994; Brooks 1995; Freynhagen 1994). In routine clinical practice, the question that arises is what really changes regarding the analgesia and tolerability of weak opioids, or low-dose strong opioids, if one or the other is used even for mild-moderate pain? Low dose oral morphine is a reliable treatment in opioid-naïve advanced cancer patients (Mercadante 2006). Maltoni et al. (Maltoni 2005) carried out a randomized prospective study in opioid naïve patients with mild-moderate pain, with the aim of evaluating the efficacy and tolerability of two different approaches: one using the second step of the ladder, the other involving moving directly from the first to the third step. Results have shown that moving from the first to the third step is associated with a reduction in the number of days with pain intensity e5 (22.8 vs 28.6%, p=0.001) or pain intensity e7 (8.6 vs 11.2%, p=0.023), however, it is also associated with an increased incidence of complications (grade III/IV anorexia and constipation).

2.4 Treatment of moderate-severe pain

In 1996, the Expert Working Group of the European Association for Palliative Care (EAPC) published guidelines on the use of morphine (EWGEAPC 1996) and in 2001 they published recommendations on the use of alternative opioids (Hanks 2001). Opioids can be given through different routes of administration (Hanks 2001; Ripamonti 2006).

Oral morphine is the drug of choice in the management of chronic moderate to severe cancer pain. The WHO expert committee introduced morphine as a major pain-relieving drug and has strongly asserted the necessity of making it available globally (WHO 1986; WHO 1996). It is considered the gold standard “step 3” opioid (WHO 1986; WHO 1996; Hanks 2004) and has been placed by WHO on its Essential Drug List (WHO 1999). The efficacy of oral morphine in repeated doses may be attributable to the entero-hepatic cycle and to the accumulation of its metabolites, especially morphine-6-glucuronide (Hanks 1987; Portenoy 1992). Ideally, two types of formulation are required: normal release (for dose titration and for breakthrough pain) and modified release (for maintenance treatment) (Hanks 2001). The dose of morphine must be titrated against effect for each patient, and the starting dose is determined by previous experience (Hanks 2001). With the use of slow (modified) release tablets the morphine administration can be reduced to twice a day; only 10% of patients find it necessary to receive the drug every eight hours (EWGEAPC 1996; Hanks 2001). In a double blind, crossover, placebo controlled clinical trial the relative analgesic efficacy and safety of an every-4-hour normal-release oral morphine (NRM) was compared to an every -12-hour modified-release oral morphine (MRM) formulation (Finn 1993). Every 12-hour administration of MRM and every 4-hour administration of NRM provide similar analgesic efficacy and side effect profiles in the treatment of chronic pain. A Cochrane systematic review on the use of oral morphine has analyzed 45 RCTs involving a total of 3,061 patients, and shown that the incidence of toxic effects was less than 4%; the most frequently reported toxic effects were nausea, constipation or drowsiness (Wiffen 2007). Morphine is the first choice opioid for moderate to severe cancer pain and the oral route is recommended as the standard option on a type 2 level of evidence. If patients are unable to take morphine orally the preferred alternative route is subcutaneous and in patients on regular doses of morphine continuous subcutaneous administration is preferable. Intravenous infusion of morphine has to be considered in all clinical instances in which the subcutaneous route is contraindicated (presence of erythema, sterile abscesses, coagulation disorders, generalized oedema) or in patients who already have an in-dwelling intravenous line (Hanks 2001; Ripamonti 2006).
Methadone is considered to be a useful alternative to oral morphine in treating moderate to severe cancer pain. Methadone is characterized by a large inter-individual variation in pharmacokinetics and by a rapid and extensive distribution phases (half-life of 2-3 hours) followed by a slow elimination phase (beta half-life of 15 to 60 hours) that may cause accumulation problems 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 in treating chronic cancer pain. Two prospective randomized trials (Ventafridda 1986; Mercadante 1998) showed overlapping analgesic efficacy and side effects for both drugs and confirmed the hypothesis that lower doses of methadone are required in comparison to morphine doses. In a double-blind study Bruera et al. (Bruera 2004) compared methadone with morphine as first line opioid in cancer pain: results were interesting but methadone did not display superiority over morphine for analgesic properties and tolerability. Methadone provides the potential to control pain that does not respond to morphine or other opioids because methadone shows incomplete cross-tolerance with other µ-opioid receptor agonist analgesics (Cherny 2001; Fitzgibbon 1997; Mercadante 2001; Ripamonti 2002). Moreover, there is the possibility of using it instead of other opioids when accumulation of active metabolite is the cause of side effects such as myoclonus, sedation, confusion, nausea and vomiting (Cherny 2001; de Stoutz 1995). Although morphine and methadone demonstrate approximately the same analgesic potency after single dose administration, in switching from one opioid to methadone a reduction of the equianalgesic dose by one-fourth to one-twelfth is recommended (Ripamonti 1998; Mercadante 1999). Methadone represents an effective alternative to oral morphine, but more caution is needed in its administration, compared with other opioids, because of marked inter-individual differences in its half-life in plasma. This option is, therefore, recommended on a type 1 level of evidence.

Hydromorphone is a semisynthetic opioid (pure agonist to µ receptors). Its average bioavailability is 50%, in the oral route of administration. No active metabolites are generated, while the principal metabolite is inactivated in the liver and then excreted by the urinary system. The potency of hydromorphone is about 5-fold (range 3 – 7,5) higher than that of morphine (Quigley 2002). Hydromorphone is a good alternative to morphine in selected patients such as those requiring higher dose of oral morphine, experiencing toxic effects or showing poor compliance to repeated daily opioid doses. Hydromorphone represents an effective alternative to oral morphine and it is recommended on a type 1 level of evidence.

Oxycodone is a synthetic opioid derived from thebaine and structurally similar to codeine. However, it is nearly 10 times as potent as codeine and about 2 times more potent than morphine (Beaver 1978; Glare 1993). It is a semisynthetic opioid (pure agonist to µ and k receptors). One slow- and one immediate–release formulation is available, the latter combined with paracetamol. A systematic review (Reid 2006) has identified 5 RCTs (Kalso 1990; Mucci-Lorusso 1998; Bruera 1998; Hagen 1997; Heiskanen 1997) directly comparing the efficacy of SR oxycodone with that of other opioids in cancer pain control: 4 studies were vs oral morphine, and one was vs hydromorphone. These studies included 20 to 101 patient series, with study duration of 6 to 18 days. A meta-analysis has combined the results from 4 of these RCTs (Reid 2006) and has not shown any statistically significant differences in terms of efficacy and tolerability between oxycodone and morphine and between oxycodone and hydromorphone. It should be noted that definitive conclusions cannot be drawn because of the limited size and time duration of the studies. No RCTs comparing combinations of oxycodone-paracetamol or of other opioids (both of the second and third step) are yet available. The real role of such associations or the possibly additional role of paracetamol to oxycodone alone, remains to be established. Oxycodone is an effective alternative to oral morphine and it is recommended on a type 1 level of evidence.

Transdermal opioids
Among opioids, the potent synthetic drug fentanyl citrate is particularly suitable for transdermal administration, and its utility in pain therapy has been extensively evaluated. In stable, chronic, cancer pain this formulation offers an interesting alternative to oral morphine (Gourlay 2001; Mystakidou 2004; Menten 2002; Radbruch 2004). In comparison with oral morphine transdermal (TTS) fentanyl seems to cause fewer gastrointestinal side effects, especially constipation (Muijsers 2001; Mystakidou 2003). Of course, this formulation is contraindicated during the titration phase, or to control breakthrough pain. TTS fentanyl is an effective alternative to morphine and it is recommended on a type 1 level of evidence.
The partial agonist buprenorphine is another ideal candidate for delivery via a transdermal patch (Bohme 2002). In the currently available formulation (buprenorphine transdermal delivery system, TDS) this drug is incorporated in a polymer adhesive matrix from which it is released through the skin. Buprenorphine TDS has been used and investigated less extensively than fentanyl TTS. The available data suggest that it may represent an effective analgesic against chronic pain (Sittl 2003). Patients who experience 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 (Cherny 2001 ; Watanabe 1997; Hanks 1997; Cherny 1995). According to Bruera et al. (Bruera 1998), the benefits of opioid switching are more likely to be related to subtle differences in pharmacology that emerge when a new opioid is substituted in a patient who has developed toxicity to another opioid than to overt differences in pharmacologic profile in patients with stable pain control. However, much more needs to be understood to answer these questions.
Spinal (epidural, intrathecal) administration of opioid analgesics in combination with local anaesthetic or clonidine should be considered in patients with unrelieved pain, neuropathic pain (Vainio 1988; Phan 2006) or intolerable adverse effects, despite the optimal use of systemic opioids and non-opioids (Kalso 1996). According to Zech et al. (Zech 1995) and Hogan et al. (Hogan 1984) only 1% to 2% of patients need spinal administration of opioids.

Transmucosal fentanyl (OTFC)
OTFC is a fentanyl lollipop that allows an immediate drug release. Analgesic effects can be achieved in 5-10 minutes (Fine 1998). Twenty-five percent of the drug is absorbed by the oral mucosa, while the rest is absorbed by the intestinal tract. Bioavailability is about 50% while the half life varies from 2,5 to 5 hours. Its use is exclusively limited to breakthrough cancer pain treatment in patients already on therapy with major opioids for cancer pain (Mercadante 2007). In the only available systematic review of breakthrough pain (Zeppetella 2006) 4 RCTs concerning OTFC have been identified: 2 RCTs have evaluated its optimal dose (titration), 1 has compared this drug with placebo and 1 including 134 patients, has compared OTFC with immediate release oral morphine. In the latter study (Coluzzi 2001) OTFC has been administered to patients already on therapy with a major opioid for cancer pain and with immediate release morphine for acute pain exacerbations. In the 14 days of the study, OTFC has shown a higher analgesic efficacy after 15 minutes, compared with morphine, allowing for a one-third reduction of pain intensity in 42% of the patients compared with a similar effect in only 32% of the patients with morphine.

Fentanyl (OTFC) is an effective treatment of breakthrough cancer pain and it is recommended on a type 1 level of evidence.

ADJUVANT DRUGS
While a large number of adjuvant drugs have been suggested to have analgesic effects, unfortunately the evidence is largely anecdotal and few controlled trials of these drugs have been conducted in cancer patients. Tricyclic antidepressants (amitriptyline, imipramine, desipramine) have shown analgesic efficacy in various neuropathic syndromes, particularly when pain has dysesthetic and paresthetic characteristics. In some controlled studies (Table 5) both amitriptyline and desipramine showed efficacy in the treatment of post-herpetic neuralgia (Watson 1982; Kishore-Kumar 1990); chlorimipramine and nortriptyline showed their efficacy in the treatment of central pain (Panerai 1990); imipramine, clomipramine, desipramine and fluoxetin proved efficient in the treatment of neuropathy-induced pain (Sindrup 1989; Sindrup 1990; Max 1992). The evidence of their efficacy in the treatment of malignant neuropathic pain is less clear. In a controlled trial vs. placebo, carried out in terminal cancer patients, the administration of imipramine was associated with a reduced quantity of required morphine (Walsh 1986). A trial period with tricyclic antidepressants is useful for patients whose neuropathic pain does not adequately respond to opioid analgesics. Tricyclic antidepressants are suitable for neuropathic pain and they are recommended on a type 1 level of evidence.

Table 5 ANTIDEPRESSANT/ANTICONVULSIVANT IN NEUROPATHIC PAIN
Table 5 ANTIDEPRESSANT/ANTICONVULSIVANT IN NEUROPATHIC PAIN
Analgesic efficacy Adverse effects
DIABETIC
NEUROPATHY
POST-HERPETIC NEURALGIA
TRICYCLIC ANTIDEPRESSANT 8 Randomized clinical trials (283 pts) analysed in a metanalysis3,5 patients should be treated in order to obtain a pain reduction by 50% in one of these pts. 3 Randomized clinical trials vs. placebo (108 pts) summarised in 2 metanalyses2 patients should be treated in order to obtain a pain reduction by 50% in one of these pts. Treatment withdrawal due to intolerance: 1 case out of 14Mild adverse effects (xerostomia, constipation, visual disturbances): 1 case out of 3
SSRI
ANTIDEPRESSANT
3 Randomized clinical trials (162 pts) analysed in a metanalysisNo difference with placebo in terms of efficacy No study available Treatment withdrawal: 2/37 ptsThe studies failed to obtain cumulative data on milds adverse effects
CARBAMAZEPINE 1 Randomized clinical study (30 pts)3 patients should be treated in order to obtain a pain reduction. No studies available
(3 Randomized clinical trials- tot 161 pts- on the treatment of trigeminal neuralgia. Results: NNT=2.6; NNH=3.7)
Drowsiness: 53% (16 pts out of 30);
Dizziness: 40% (12 pts out of 30)
Treatment withdrawal: 10% (3 pts out of 30)
PHENYTOIN 2 Randomized clinical trials (~ 52 pts)
Contrasting results (1 study indicates a difference, which is not confirmed by the other study)
No studies available Mild adverse effects (drowsiness, dysequilibrium, walking instability): 1 case out of 3
GABAPENTIN 3 Randomized clinical trials (40- 28-165 pts)
(2 studies indicate no difference, 1 larget study shows a pain reduction in favour of gabapetin vs. placebo, after 8 weeks)
2 randomized clinical trisls (334 pts)
Gabapetin proved more efficacy than placebo after 7-8 weeks at doses comprised between 1800 and 3600 mg/die
Mild adverse effects
drowsiness
up to 24%
dizziness up to 33%
PREGABALIN 1 Randomized clinical trial, Pregabalin was tested for 8 weeks vs placebo, showing a pain reduction by 1.5 points vs placebo (with 0-10 number scale) 2 Randomized clinical trials Pregabalin was tested for 8 weeks vs placebo, showing a pain reduction by 1.5 points vs placebo (with 0-10 number scale) Adverse effects were not severe but frequent
Dizziness:
up to 36%
Drowsiness: up to 25%
Peripheral oedema: up to19%

Corticosteroids are frequently administered to cancer patients but their efficacy in inducing pain relief has been shown only in a limited number of studies (Bruera 1985; Della Cuna 1989; Moertel 1974; Popiela 1989). They are likely to exert their effect by decreasing peritumoral oedema and signs of inflammation, which in turn, may reduce peripheral nerve stimulation. Dexamethasone has shown to be effective in alleviating metastatic spinal cord compression (Vecht 1989) and in treating headache related to endocranial hypertension. Corticosteroids are standard option on a type C basis.

Anticonvulsivants: (carbamazepine, phenytoin, valproic acid, clonazepam, gabapentin) are all drugs utilized in the treatment of neuropathic pain with a component referred as “lancing” or “lancinating”. Clinical experiences (Table 5) have been reported concerning the use of these drugs in the treatment of neuropathic pain caused by diabetes, radiotherapy induced fibrosis or surgical lesions, herpes zoster and deafferentation (Swerdlow 1985; Rosemberg 1997; Rice 2001; Rowbotham 1998; Backonja 1998; Gorson 1999; Morello 1999; Dworkin 2003; Sabatowski 2004; Rosenstock 2004; Wiffen 2000; Nonino 2004; Alper 2002; Collins 2000; Challapalli 2005). Clear evidence of their possible efficacy in neuropathic cancer pain is lacking. Only one RCT, including 121 patients, is available (Caraceni 2004); this assessed the role of gabapentin in the treatment of neuropathic cancer pain. The study showed a significant difference in average pain intensity between gabapentin (pain score, 4.6) and placebo groups (pain score, 5.4; P = .0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P = .0077). Gabapentin appears effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids. There is a lack of published studies aimed at directly comparing the two different drugs and therefore a precise estimate of which drug is most effective is not possible. Carbamazepine in neuropathic pain is recommended on a type 1 level of evidence. Gabapentin in neuropathic pain is recommended on a type 2 level of evidence.

Local anesthetics: studies of the efficacy of intravenous and subcutaneous administration of lidocaine in patients with neuropathic cancer pain have shown contradictory results (Kastrup 1987; Bach 1990; Ferrante 1996; Galer 1993; Brose 1991; Elleman 1989; Bruera 1992). Evaluating pain relief and adverse effect rates with systemic local anesthetic-type drugs and other control interventions, a Cochrane review (Challapalli 2005) has shown that 32 controlled clinical trials met the selection criteria, among which, 21 were crossover, while nine were parallel studies. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Lidocaine and mexiletine were superior to placebo, and, data, although limited, showed no differences in efficacy or in adverse event rates compared with carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. The overall conclusion from the Cochrane review was that lidocaine and oral analogues were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and as effective as other analgesics. Future trials should enrol patients with specific diseases and evalauate novel lidocaine analogues with better toxicity profiles. Local anaesthetics for neuropathic pain are suitable for individual clinical use on a type 2 level of evidence.

Bisphosphonates

Several studies have demonstrated the role of bisphosphonates either in preventing serious skeletal complications, or in reducing the frequency of orthopaedic surgical interventions for fractures or the need for radiation therapy (RT), or in alleviating pain (Kohno 2005; Nigro 2004; Saad 2004; Rosen 2003; Wardley 2005; Carteni 2006; Eastham 2005; Wong 2002; Small 2003; Groff 2001; Hortobayi 1996; Fulfaro 1998; Mancini 2004; Wellington 2003) in patients with painful bone metastases due to solid tumours who are treated according to American Society of Clinical Oncology (ASCO) guidelines (Hillner 2003). Evaluating the role of bisphosphonates in achieving pain relief in patients with bone metastases, a Cochrane review (Wong 2002) has identified 30 randomized controlled studies (21 blinded, four open and five active control), including a total of 3682 subjects. Pooled data for the proportion of patients with pain relief (eight studies) showed benefits for the treatment group, with an NNT (number needed to treat) at 4 weeks of 11 [95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH(number needed to harm) was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for a greater risk in the treatment group. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. The overall conclusion from the Cochrane review was that there is enough evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect, as first line therapy. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases. Bisphosphonates in pain from bone metastases are recommended on a type 2 level of evidence.

Radioisotopes

For patients with widespread bone metastases and bone pain, who are difficult to manage with external radiotherapy, systemic therapy using beta-emitting radiopharmaceuticals must be considered as a valuable and effective palliative treatment option (Liepe 2005; Finlay 2005). Strontium-89, samarium-153, rhenium-186, and rhenium-188 are the radioisotopes used in clinical practice that emit â particles. They are deposited and concentrated in areas of active bone turnover; thus all metastases are treated at the same time, at a rate ranging from 4:1 to 17:1 in comparison with normal bone (Pandit-Taskar 2004). Studies comparing the efficacy of the various radioisotopes did not show significant differences (Serafini 1998; Resche 1997; Sartor 2004; Farhanghi 1992 ; Tian 1999 ; Serafini 2000; Maini 2004; Roque’ 2003). The mechanism responsible for pain relief is as yet not completely understood. A possible explanation is that the radiation-induced tumour necrosis decreases the number of cells involved in the inflammatory and immunological reactions consequently reducing chemical mediators that increase pain perception such as prostaglandins, substance P, bradykinins, interleukins and tumour necrosis factors. It is not clear whether radioisotopes have a tumouricidal effect as well. Among the bone-seeking radiopharmaceutical agents, 153-samarium is a low-beta-energy emitter (maximum beta energy of 0.81 MeV) with low marrow toxicity when used with palliative intent. A number of controlled and uncontrolled studies have demonstrated that 1mCi/kg 153-samarium-lexidronam is active in the relief of pain associated with metastatic bone lesions deriving from several tumour types (Serafini 1998; Resche 1997; Sartor 2004; Farhanghi 1992; Tian 1999 ; Serafini 2000; Maini 2004; Roque’ 2003). Data in the literature show that effective pain palliation was obtained in 73 to 86% of patients treated with 153-samarium (Resche 1997; Enrique 2002; Turner 1991). In 417 patients treated with 153-Sm, 73% of them had good pain control and 82% of these patients could reduce their analgesic intake substantially or completely; moreover in 50% of these patients pain relief lasted for more than 8 weeks (Enrique 2002). Pain relief was obtained within 5-10 days after samarium infusion and lasted up to 4 months in some patients. However, no prospective studies carried out on radioisotopes specifically assessed the role of this class of drugs in preventing or reducing movement-related pain (incident pain) (Finlay 2005; Roque’ 2003), which is the most frequent pain in patients with bone metastases (Caraceni 1999). Radioisotopes in pain from bone metastases are a recommended option on a type 2 level of evidence.

2.5 Treating cancer pain: is it istill a medical problem?

Despite the fact that cancer-related pain can be well or completely controlled if the published clinical recommendations are followed (WHO 1986; WHO 1996; EWGEAPC 1996; Hanks 2001; Jacox 1994), unrelieved pain continues to be a substantial worldwide public health concern (Hearn 2003; O’Mahoney 2003). Pain associated with cancer is frequently undertreated in children as well (Miser 1987). Younger patients, patients without metastatic disease, patients with a better performance status, and patients who rate their pain as more severe than their doctors do, are at greater risk for undertreatment of their pain (Larue 1995). A discrepancy between patient and physician in judging the severity of the patient’s pain is predictive of inadequate pain management (Cleeland 1994). This is a big setback for positive pain control as pain is an extremely subjective symptom and only the patient can describe the intensity and magnitude of his/her personal experience of pain. There is still great reluctance to prescribe opioid analgesics for fear of the patient developing addiction, tolerance or side effects (Larue 1995; Zenz 1993). Moreover, among cancer patients morphine is often considered as a last resort (Reid 2008). Addiction is rare in patients with no addiction history. Out of 11,882 patients treated with opioids, there were only four cases of documented addiction in patients who had no previous history of addiction (Porter 1980). Another difficulty for adequate analgesia is that the treatment of cancer pain is still not considered of first importance in the heath care system and additionally analgesics are often costly, not refundable, and not easily available in some countries of the world. Treating cancer-related pain is often addressed only for advanced and terminal cancer patients and not for patients whose condition is stable, whose life expectancy is long and who are still undergoing chemo- or radio-therapy treatment. The burden is increased since there is still an inadequate knowledge of pain assessment and management (Von Roenn 1993) and restrictive regulation of opioids as controlled substances (Joranson 1992).

2.6 Conclusions

Successful pain management requires treatment of what Dame Cecily Saunders described as the patient’s TOTAL PAIN: physical, psychological, social, spiritual and cultural. 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. 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.

INDEX

 

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Dr. Elena Bandieri (Author)
Carpi Mirandola Hospital and CeVEAS – Modena, Italy
mail: e.bandieri@ausl.mo.it

Dr. Carla Ripamonti (Author)
IRCCS Foundation National Cancer Institute – Milan, Italy
mail: carla.ripamonti@istitutotumori.mi.it

Dr. Carla Ripamonti (Reviewer)
IRCCS Foundation National Cancer Institute – Milan, Italy
mail: carla.ripamonti@istitutotumori.mi.it