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 »  Abstract
 » Introduction
 »  Pain Syndromes R...
 »  Iatrogenic and C...
 »  Diagnostic Asses...
 »  Pain Management ...
 »  Pharmacological-...
 »  Nonpharmacologic...
 »  Conclusions and ...
 »  References
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Table of Contents 
Year : 2011  |  Volume : 17  |  Issue : 3  |  Page : 175-183

Pain in blood cancers

1 Department of Hematology, S. Eugenio Hospital, Rome, Italy
2 Department of Radiation and Radiotherapy, University of Rome La Sapienza, Rome, Italy

Date of Web Publication28-Jan-2012

Correspondence Address:
Pasquale Niscola
Department of Hematology, S. Eugenio Hospital, Rome
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1075.92333

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 » Abstract 

Patients with blood-related cancers (BRC) suffer from a substantial symptom burden, including several pain syndromes sustained by different causes and pathogenetic mechanisms. So, with regard to pain, a multifaceted clinical scenario may be observed in this setting. Indeed, pain may be correlated to disease itself, to disease-associated complications, to iatrogenic causes or may be due to unrelated clinical conditions. A close diagnostic procedure for the assessment of the underlying causes of the pain and of its pathogenetic mechanisms may direct the treatment approach which should be based on a multidisciplinary management and requires the integration of etiology-targeted interventions and painkilling drugs. The World Health Organization's three-step analgesic ladder for cancer pain relief can provide adequate pain control using oral drugs in most patients with BRC on pain, although more complex interventions may be necessary for many difficult-to-treat pain syndromes which are not infrequently encountered in this setting.

Keywords: Blood-related cancers, Hematological malignancies, Pain

How to cite this article:
Niscola P, Tendas A, Scaramucci L, Giovannini M, De Sanctis V. Pain in blood cancers. Indian J Palliat Care 2011;17:175-83

How to cite this URL:
Niscola P, Tendas A, Scaramucci L, Giovannini M, De Sanctis V. Pain in blood cancers. Indian J Palliat Care [serial online] 2011 [cited 2020 Sep 20];17:175-83. Available from:

 » Introduction Top

Patients with blood-related cancers (BRC) have a substantial symptom burden, [1],[2],[3] including some kinds of pain. [4],[5],[6],[7] Several pain syndromes, which may be due to disease itself, to its complications, to diagnostic procedures and treatments [8] may be recognized in this setting [Table 1]. Pain is defined as acute or chronic with regard to its temporal pattern; from a neurobiological point of view, it is classified as nociceptive (inflammatory) or neuropathic. In addition, the nociceptive pain can be divided into somatic (superficial and deep) or visceral [Table 1]. Moreover, in some instances, pain may also occur in the absence of any recognizable noxious stimulus, [9] resulting from a centrally maintained process related to a complex lesion in the somatosensory pathways in which some neurobiological changes, such as the activation and plasticity of neuronal and glia cells, are likely involved. [10] Again, breakthrough pain, representing an intermittent exacerbation of pain which may occur either spontaneously or evoked by movements (incident pain), [11] is frequently encountered in the setting of malignant hematology. [12] In this regard, it is important to take into account that incident pain is a pain due to movement in any clinical condition, whereas movement breakthrough incident pain is a pain due to movement but in a patient treated with a continuous opioid therapy. In patients with BRC, pain may be frequently observed as a presenting symptom at the disease onset; [13] this kind of pain generally responds well to causal measures and usually relief from this pain occurs soon after the commencement of a treatment with chemotherapeutic agents and/or steroids. On the other hand, patients under active treatment can complain iatrogenic pains of short or long duration; [8],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] moreover, survivor patients may experience chronic pain due to treatment-related complications. [26] Lastly, in advanced-stage patients with incurable disease, pain represents one of the most distressing symptoms that would be managed in the contest of a comprehensive program of end-life care. [6] Pain has traditionally represented a neglected issue in malignant hematology. [8],[27] Thus far, in default of specifically dedicated guidelines, pain management in oncohematological patients is derived from those used for the patients affected by solid tumors. As it has been recently reported, cancer pain has been frequently under-recognized and mismanaged. [28],[29] Therefore, the same considerations about an inadequate pain control may be translated also in the setting of malignant hematology, although it has firmly stated that a comprehensive pain treatment should be included in the global management of patients with BRC. [27] Epidemiological data on pain syndromes in patients with BRC are scanty and sparse. In the past, several authors have reported a much lower incidence and severity of pain in patients with BRC with respect to those recorded in the setting of solid tumors; [30] however, the former setting a pain incidence ranging from 37 to 90% [1],[2],[3],[4],[5],[6],[7],[13],[31],[32],[33],[34] have been reported, for which the occurrence of pain in patients affected by BRC may be considered as similar or even higher compared to patients with solid tumors . [5],[6],[7],[31] This review attempts to cover the topic of pain in patients suffering from BRC, which has been much neglected in the past.
Table 1: Pain syndromes in blood-related cancers

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 » Pain Syndromes Related to Blood Cancers and Their Complications Top

The most important disease-related pain experienced by patients with BRC is represented by bone pain [Table 1] which is essentially related to two pathological processes: osteolytic lesions and the infiltration of bone marrow (BM) by malignant cells. [8] In these circumstances, pain is originated by the activation of sensory and sympathetic nerve fibers that extensively supply the periosteum, the mineralized bone and the BM. [35] Among patients with BRC, those affected by multiple myeloma experience the most distressing pain syndromes of bony origin. [14] Other than the skeletal involvement, pain may be due to its complications, such as the physical deconditioning syndrome, which is characterized by muscle atrophy and physical debility that produce bedsores, constipation, rectal and bladder spasms with a negative impact on the quality of life. As mentioned earlier, skeletal lesions generate localized and/or irradiated nociceptive continuous pain at rest, sometimes complicated by neuropathic symptoms (mixed pain), and movement-related incident pain. In the absence of skeletal lesions, BM hypertension, ischemia, and the strength of the periosteum due to the BM involvement by malignant cells are the traditionally supposed mechanisms of pain. [8] However, recently, some experimental data from animal models have changed these hypotheses, which demonstrate the generation of the pain by the sole presence of malignant cells in the BM and/or in the mineralized matrix, in the absence of any recognizable periosteal tumor involvement and/or lytic lesions. [35] Patients with BM infiltration usually describe a dull or throbbing deep and often migrating pain. Other well-known causes of disease-related pains [Table 1] are represented by visceral, cutaneous and mucus membrane tumor involvement, space-occupying masses, bulky lymph [8] nodes and organ enlargements [36],[37] as well as peripheral nerve injuries. [14],[25] Other important causes of neuropathic pain are the involvement of vertebral bodies with extradural compression of spinal cord observed in multiple myeloma and lymphomas (more rarely in other BRC) as well as infiltration/compression by cervical, axillary, para-aortic or retroperitoneal lymph nodes of adjacent nervous plexus. Some other important pain syndromes may be related to clinical complications of BRC. Indeed, oncohematological patients are highly predisposed to painful infections, such as pneumonia, cellulitis, urinary tract infection, wound infections, oral and gastrointestinal mucositis, esophagitis by Candida, oral and genital herpes, herpes zoster and postherpetic neuralgia. Lastly, deep or superficial vein thrombosis and internal hemorrhages may occur, causing different kinds of pain based on the involved pathological mechanisms and anatomical region.

 » Iatrogenic and Care-Related Pain Syndromes in Patients with Blood Cancers Top

Pain of iatrogenic and care-related origin represents a growing concern in oncohematology. Discomfort and transient acute pain afflict virtually almost all patients submitted to invasive diagnostic procedures, [8],[14] such as the lumbar puncture (headache) and the BM aspiration/biopsy, [15],[16] as well as to other care-related maneuvers, such as vein punctures, the placement of catheters, medications, the patient's mobilization/transportation and so on. Moreover, agents commonly used to treat BRC may induce several kinds of pain [Table 1]. Indeed, patients who are receiving granulocyte colony-stimulating factors (G-CSFs) for neutropenia or stem cell mobilization may suffer bone pain and headaches due to expansion of the hematopoietic matrix and the sensitization of nerve endings in the BM. [17] In addition, therapy-related skeletal morbidity, including steroid-induced myalgias and bone changes and the osteonecrosis of the jaw caused by biphosphonates, represents an important source of pain [14],[18],[20] [Table 1]. Oral mucositis induced by chemotherapeutic regimens, in particular by those included in conditioning regimens for hematopoietic stem cell transplantation (HSCT), is the most frequently recorded therapy-related pain of superficial somatic origin experienced by patients with BRC. [21],[22] Moreover, gastrointestinal mucositis is frequently associated with visceral pain. In patients who have undergone allogeneic HSCT, the mucosal damage induced by graft versus host disease (GVHD) has a similar appearance to that caused by cytotoxic drugs. Again, intestinal involvement by GVHD represents another well-known source of visceral pain. In addition, other specific drugs, such as l-asparaginase and bortezomib which may induce acute pancreatitis, [23] and intestinal neuropathy and visceral dismotility, [14] respectively, are well-known causes of therapy-related visceral pains. Again, other neurotoxic drugs like thalidomide and vincristine [24] may induce constipation which represents another important cause of visceral pain. Lastly, another frequent source of visceral pain is the urinary bladder irritation and/or hemorrhagic cystitis observed in allogenic HSCT patients, mainly in those conditioned with total body irradiation (TBI) and cyclophosphamide-containing regimens, [21] whereas in the setting of standard and high-dose chemotherapy, these painful urological complications may be potentially induced by cyclophosphamide and ifosfamide. Pain syndromes of neuropathic origin are mainly due to peripheral neuropathies induced by novel agents, such as thalidomide and bortezomib, [14],[25] as well as due to traditional compounds, such as platinum analogues and vinca alkaloids. [8] Lastly, drugs used for GVHD prophylaxis, such as calcineurin inhibitors, may induce neurotoxicity and neuropathic pain. [19]

 » Diagnostic Assessment of Pain in Patients with Blood Cancers Top

Patients with BRC can suffer from several kinds of pain, sometimes coexisting in the same patient. A separate assessment of each pain syndrome is mandatory for an optimal management. Pain should be regularly evaluated as the 5 th vital sign. Reporting of patients about their pain experience is the primary step for the pain assessment. The pain intensity can be recorded by several tools, such as verbal descriptions, the visual analogue score (VAS) and the numerical rating scale (NRS). [38] These tools may be inappropriate for some patients, such as pediatric, non-communicative and unconscious adult patients, for whom facial expressions and verbal and non-verbal descriptors can be used. [38] The evaluation and the assessment of neuropathic pain are based on specific instruments and scales. [39] The cause of pain should be diagnosed as the primary step in order to optimize a patogenetically target-oriented treatment. In this regard, radiologic imaging and electrophysiological studies can be useful in selected circumstances. Conventional radiology, including an X-ray of the skeleton, computed tomography (CT) and magnetic resonance imaging (MRI) represent the standard diagnostic methods for the detection of symptomatic or asymptomatic osteolytic lesions and spinal cord compression. [14] Moreover, CT and MRI are employed for the assessment of bisphosphonate-induced osteonecrosis of the jaw. Electrophysiological studies, based on the nerve conduction velocities evaluation, such as specific latency time, amplitude, duration, and configuration of sensory- and motor-evoked potentials, and neurological clinical evaluation can allow identifying the origins and severity of the underlying neuropathic disorders. [25],[39]

 » Pain Management in Oncohematology Top

Whenever possible, in patients with BRC, pain should be prevented. In those with pain, a rational treatment strategy should be based on causal interventions along with analgesic measures. So, chemotherapy and radiotherapy represent the mainstay treatments of underlying disease-related painful conditions; moreover, antibiotics should be given to control infections, whereas orthopedic devices as well as skeletal-stabilizing surgical procedures and physiotherapy can be useful in selected circumstances. [40],[41],[42]

Preventive measures

Over the last decade, increased use of bisphosphonates has provided an effective measure to prevent the manifestations of myeloma bone disease. [14],[43] On the other hand, the prevention of procedural and iatrogenic pain remains a very difficult task. Diagnostic procedures of short duration, such as lumbar puncture and BM aspiration/biopsy, are usually performed under local anesthesia; however, they may be poorly tolerated by some patients. Therefore, in these selected cases, a pre-emptive analgesia with brief unconscious sedation [8],[25] or general anesthesia [44] can be advised. The prevention of oral and gastrointestinal mucositis, unfortunately, remains still unsatisfactory; a careful oral hygiene and the patient's education represent the only recommended measures. [22] Oral cryotherapy has been reported as an effective intervention to prevent oral mucositis in patients receiving a short-lasting agent, like melphalan, prior to the autologous HSCT. Finally, the human recombinant keratinocyte growth factor, palifermin, is the only preventive measure approved exclusively in the setting of autologous HSCT when TBI is included as part of the conditioning regimen. [22] Constipation due to neuropathic drugs like vincristine is difficult to manage; its prevention may be based on a careful dose adjustment of vincristine and avoiding the co-administration of several drugs, such as itraconazole, which interfere with its metabolism and elimination by inhibition of CYP3A enzymes. [24] No preventive measures are available for therapy-induced peripheral neuropathies and its management relies on a careful patient evaluation and follow-up; in patients treated with bortezomib, early dose reduction or the discontinuation of neurotoxic agents may avoid the progression of the neural damage and allows to achieve at least a partial recovery of nerve dysfunction. [25]

Causal and interventional measures

Induction chemotherapy can be considered as an "etiologic measure" due to its powerful effect not only in relieving pain, especially malignant bone pain, but also in relieving the pain due to the disease burden, which responds dramatically to it in most cases. Also, corticosteroids can be considered a targeted-oriented treatment for most BRC, especially for those of lymphoid . Other than relieving bone pain, corticosteroids are particularly effective when pain is related to neural infiltration or compression of neural structures, as observed in patients with spinal cord compression, in which high doses of dexamethasone can result in a sudden pain relief; moreover, corticosteroids along with mannitol can have a critical role in patients with meningopathies and/or brain disease involvement by reduction of intracranial pressure; again, the compressing effects to adjacent structures by enlarged lymph nodes can be relieved by these agents. Chemotherapy should be employed according to the patient's performance status, also with a palliative intent, based on the sensitivity of most BRC to anti-neoplastic agents even in the advanced phase of disease. The block of inflammatory cytokines' secretion by malignant cells, the reduction of the peritumoral edema and the control of the BM expansion, other than the direct reduction of tumor burden, are all the mechanisms likely to be involved in pain relief provided by chemotherapy and corticosteroids. Painful manifestations of myeloma bone disease can be treated with specific and targeted measures as biphosphonates which exert also an analgesic activity . [14],[43]. Radiotherapy is effective to control pain due to bony lesions and to to spinal cord compression. [8],[14] Several radiotherapic regimens, differing in the fractionation schedules, are usually employed in clinical practice, according to the clinical aims and the different radiobiological basis of pain response and re-calcification process. Therefore, with regard exclusively to pain relief, a more simple and convenient 8 Gy single fraction is recommended for the palliation of localized painful bony lesions, especially in the case of low patient's performance status and short life expectancy. The multiple-fraction schedules given over a longer time (i.e. 40-44 Gy/20-22 fractions/4 weeks, or 30 Gy/10 fractions/2 weeks) are reserved to patients with a long life expectancy and these schedules provide the best pain relief and also the reconstitution of the bone structure. [14] Lastly, outside the setting of skeletal pain, palliative radiotherapy at lower doses (6-10 Gy total dose with 0.4-1 Gy/fraction) [36],[37] has been successfully applied to relieve the symptoms associated with splenomegaly and for the palliation of bulky nodal masses (4 Gy/2 fractions). [45] For patients with large osteolytic lesions in weight-bearing bones, orthopedic devices and surgery procedures may achieve pain control and prevention of impending fractures. In recent years, percutaneous cementoplasty, vertebroplasty and kyphoplasty have been developed to repair spinal fractures and to provide pain relief in patients with multiple myeloma (MM) [14],[46].

 » Pharmacological-Based Pain Management in Oncohematology Top

As for the treatment of pain from solid tumors, pharmacological management of pain in patients with BRC may include analgesic (opioid and non-opioid) and adjuvant agents whose selection should be based on the diagnosis of the kind of pain (nociceptive, neuropathic and breakthrough) and its intensity. Some patient-related variables, such as the performance status, comorbidities (i.e. renal failure, hepatic impairment, peptic ulcer, psychiatric illness, cardiovascular disease, diabetes mellitus and other chronic illnesses), [47],[48],[49] and concurrent medications (i.e. polypharmacy and the risk of drug interactions), should be taken carefully into account for their possible influence on the efficacy and tolerability of analgesic treatment. [Table 2] lists the most widely employed drugs and the starting drug dose for patients with BRC. The effectiveness in the pain management provided by the World Health Organization (WHO) analgesic ladder [50] in these patients has been reported. [6],[34] The patient's compliance and the urgency to achieve the pain control are of paramount importance for the choice of administration route. Although the oral route is preferred by most patients, alternative ways of administration (rectal, subcutaneous, sublingual and so on) can be considered. [51] The intravenous route is the fastest method to achieve analgesia in patients with rapidly escalating or otherwise uncontrolled pain. [52] Intravenous morphine by patient-controlled analgesia (PCA) systems represents the method of choice to control pain in patients with oral mucositis. [30],[31],[42] A fast pain relief can be achieved also by a strongly lipophilic opioid agent with a rapid analgesic onset, such as fentanyl, which is available in preparations suitable for transmucosal, buccal, sublingual and intranasal routes [53],[54] to treat the breakthrough pain. But the use of these fentanyl preparations requires high caution and they should be given only to opioid-tolerant patients receiving doses of oral morphine equivalents of at least 60 mg; however, the doses to be recommended have not been firmly established. [55] The transdermal route can be optimal in patients who reached a stably maintained analgesia and it is not indicated when a fast titration is required or when the pain relief should be urgently achieved, although low doses of transdermal fentanyl have been safely and effectively given to opioid-naive patients with cancer pain. [56] The intramuscular route is generally discouraged because of the pain related to procedure itself, the erratic drug absorption and pre-existing coagulative disorders. Finally, invasive procedures for neuraxial opioid deliveries are very rarely performed in patients with BRC, given the frequent occurrence of neutropenia and thrombocytopenia. [8]
Table 2: Analgesic and adjuvant drugs dosing in hematological malignancies

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Non-opioid agents

Standard analgesics, such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, can be reserved for nociceptive pain. In the management of mild-to-moderate pain experienced by patients with BRC, paracetamol plays a key role. This agent does not inhibit peripheral prostaglandins, and therefore does not exert any influence on the coagulative system; so, it shows a safer profile than NSAIDs, although its use requires attention in the presence of hepatic impairment. [47],[49] NSAIDs are particularly effective in relieving bone pain [57] which is a common finding, particularly in patients with BRC; however, the occurrence of renal dysfunctions and the presence of an elevated risk of bleeding due to thrombocytopenia are frequently encountered in this setting because of which the use of these agents requires caution. Among the NSAIDs, COX-2 inhibitors may be considered as suitable agents for long-term therapy of chronic pain in patients with coagulative disorders because they exert no influence on the hemostatic system. In this regard, although no studies on the use of these agents in the setting of BRC have been reported until now, celecoxib has been reported as effective in treating chronic synovitis and joint pain in hemophiliacs. [58] However, several reports have pointed at the cardiovascular and renal adverse effects that these agents may cause. Therefore, given the specific clinical features recorded in BRC, the use of NSAIDs should be carefully evaluated and, whenever possible, they should be replaced with other drugs, such as paracetamol or weak opioids. Lastly, a warning to the administration of paracetamol and NSAIDs concerns the management of neutropenic patients because they may mask the fever and an underlying septic condition.

Opioid agents

According to the pain intensity (moderate or severe) for which their use is recommended, [51],[59],[60],[61] opioids are classified as weak and strong opioids [Table 2]. Therapy with opioids needs a wide knowledge of potency of each of them, defined with respect to the potency of morphine, considered as the "reference point" of analgesic effect of all opioid drugs. Moreover, the knowledge of bioavailability of each opioid by the chosen route of administration and a careful titration in each patient are mandatory. For titration, small starting doses of a short half-life agent are advisable. Constipation is one of the most frequent untoward effects in patients who receive opioids for 3 or more days; in this regard, a prophylactic regimen (i.e. senna plus docusate, macrogol and so on) for opioid bowel dysfunction should be prescribed. [62] Moreover, in case of unexpected adverse effects, current recommendations underline the need for a careful clinical evaluation of the patients in order to distinguish true opioid-related adverse events from other clinical conditions, such as comorbidities, dehydration or drug interactions, before to definitively stop therapy with opioids. In fact, appropriate opioid dose reduction with eventual addition of other adjuvant agents or a cross with another opiod drug, according to the equivalent conversion dose table, should be considered in these circumstances. [63]

Treatment of neuropathic pain and adjuvant agents

Adjuvant analgesic drugs include any agent with a main therapeutic indication different from pain relief but with a capability to provide pain control also. These drugs are of critical relevance in the management of all kinds of pain and are particularly used for pain relief in the setting of neuropathic conditions. The most frequently employed adjuvant agents in patients with BRC are bisphosphonates as well as antidepressants and anticonvulsants, such as gabapentin and pregabalin [Table 2], which are given for several neuropathic conditions, for which the treatment may require an individualized management with tricyclic antidepressants, anticonvulsants and some opioid drugs, as single agents or in combination. [25],[39]

 » Nonpharmacological Approaches Top

Several nonpharmacological approaches can be useful in the management of pain and they can provide some benefits, although no controlled studies have been reported in patients with BRC. A psychological support and multimodal cognitive behavioral interventions, including relaxation techniques, coping strategies, and mood-enhancement strategies, should be taken into account when a comprehensive pain management is planned. Moreover, physical therapies, rehabilitation and other biomechanical interventions (massage and trigger point pressure) [40],[42] may have a role in relieving some kinds of pain and their disabling complications.

 » Conclusions and Perspective Top

The control of pain is an essential condition in the global management of not only the patients with active BRC but also long survivors, in whom the improvement of quality of life is a topic of paramount importance. In this regard, an appropriate pain management should possibly be based on a multidisciplinary approach. The WHO analgesic ladder for cancer pain is effective in most cases, although adjuvant agents, targeted measures and nonpharmacological interventions may play a critical role in relieving pain in selected circumstances. In the prevention of pain is the current challenge. In this regard, in the last decade we have achieved promising clinical benefit in the prevention and treatment of myeloma bone disease, . Moreover, among the immunomodulatory drugs used to treat especially the patients with multiple myeloma, lenalidomide and the other analogues currently under investigation, such as pomalidomide, have been demonstrated to induce no neurotoxic effects. [23] In conclusion, a better understanding of the variables associated with the response to analgesic treatment, [64],[65] allowing the identification of difficult-to-treat patients, can lead to improve our clinical practice in the setting of malignant pain. In this regard, advances in the knowledge of the molecular basis of pain may provide promising development of new diagnostic tools and targeted therapeutic intervention, [62],[66] possibly translating into significant improvement of pain management in the near future.

 » References Top

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  [Table 1], [Table 2]

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