Introduction

Pain is a major symptom in patients undergoing haematopoietic stem cell transplantation (HSCT) for haematological malignancies.^{1, 2} Several pain syndromes of different pathophysiology and severity have been reported.³ Stem cell donors may experience pain from mobilization of haematopoietic stem cells or collection of bone marrow.⁴ The major cause of pain in HSCT recipients is a result of injury to mucosal tissues induced by the conditioning regimen.⁵

In addition, pain in HSCT recipients may be due to infection, acute and chronic GVHD as well as adverse effects of some of the drugs administered for GVHD prophylaxis. Furthermore, some late complications of HSCT may be associated with pain.

Methods

We systematically searched the English, French and Italian medical literature using one or combinations of the following subject headings of the National Library of Medicine in Medline (MeSH headings) found in the title of the article and its abstract or among its keywords: pain, haematopoietic stem cell transplantation, haematology, haematological malignancies, palliative care, quality of life, analgesics, opioids, morphine, mucositis and patient-controlled analgesia (PCA). The retrieved articles were then studied and selected for further assessment if the document reported the diagnosis and the treatment of pain in HSCT patients. The bibliography of each retrieved article was also scanned to identify additional papers that fulfilled the inclusion criteria and which could contribute to the literature review. We also scanned abstracts and published proceedings of pain and HSCT meetings, and preferentially selected specific reports on pain syndromes in the HSCT setting. We also reviewed and selected articles dealing with general pain issues to obtain useful background information for this review article.

Epidemiology and causal factors of specific pain syndromes in HSCT patients

The aetiology of HSCT-related pain syndromes can be categorized according to their appearance during the time course of the transplantation procedure. Pain may occur at any transplant-related phase, such as stem cell mobilization, the conditioning phase, haematological recovery and the late post transplant period (Table 1).

Table 1 - HSCT-related pain syndromes: their origins and pathogenesis.

Full table

Mobilization and harvest of haematopoietic stem cells

Bone pain and, less frequently, headache following stimulation with filgrastim have been recorded in 24% of stimulated patients.⁶ Recently, several reports have been published claiming that a low frequency of mild bone pain occurs after pegfilgrastim treatment in patients with non-Hodgkin's lymphoma^{7, 8} and multiple myeloma.⁹ In allogeneic HSCT, a significantly lower incidence of severe pain has been reported by blood cell donors compared with marrow donors (85 vs 68% , P=0.02). The median duration of pain was 14 days after a marrow harvest and 3 days after blood cell mobilization. In addition, pain lasting more than 7 days was reported by a larger number of marrow donors than by those who underwent blood cell collection.⁴ A comparative study reported that the incidence of bone pain was 65.3% in donors receiving lenograstim and 61.9% in those stimulated with filgrastim.¹⁰ A rare but painful acute complication of filgrastim stimulation, seen in patients¹¹ and healthy donors,¹² is rupture of the spleen. Pegfilgrastim-stimulated donors have reported mild pain with characteristics similar to that reported by patients stimulated with filgrastim.^{13, 14}

In the setting of a marrow harvest, the reported incidence of pain is 31% .¹⁵ Total 86% of marrow donors who had experienced prolonged post-harvest pain and who underwent magnetic resonance imaging 1 year after the harvest had abnormal findings that included the persistence of the 'acute injury' signal pattern and signal alterations due to fatty marrow conversion.¹⁶

Ahlmann et al.¹⁷ reported that the pain was significantly more severe and prolonged after a marrow harvest from the anterior iliac crest than after a marrow harvest from the posterior iliac crest. In addition, a marrow harvest may occasionally be followed by compressive neuropathies affecting the sciatic nerve¹⁸ and the sacral plexus¹⁹ due to the development of haematomas.

Pain syndromes developing from the start of the conditioning regimen to day 100

While the administration of conventional chemotherapeutic agents (CHT) generally does not cause pain, radiotherapy may cause a painful inflammatory skin reaction (radiation dermatitis). The infusion of haematopoietic stem cell (HSC) may cause acute adverse reactions, such as abdominal cramps, thoracic pain and headache due to DMSO toxicity.²⁰ However, the most intense pain occurs during the early post transplant period and usually is a reflection of the site and severity of the mucosal injury.⁵

The occurrence of oral mucositis (OM) was significantly higher in patients with haematological malignancies who were infused with autologous HSCT than those who had solid tumours and underwent the same procedure.²¹

The severity of OM is closely correlated with the conditioning regimen,²² and has been reported to be as high as 75% in lymphoma patients conditioned with carmustine, etoposide, cytarabine and melphalan regimen.²³

The association of idarubicin with BU for autologous HSCT in patients with AML caused profound mucosal derangement and pain in 82% of patients.²⁴

In myeloma patients, a high dose (200 mg/m²) of melphalan is associated with a 30–35% incidence of OM.²⁵ Conversely, the reported incidence of severe OM associated with intermediate doses of melphalan (100 mg/m²) in myeloma patients is under 10% .²⁶ In the setting of allogeneic HSCT, a study on 429 transplanted patients reported OM in almost all patients; grade III or IV in 67% . The only independent risk factor significantly associated with OM was the conditioning regimen; high doses of melphalan resulted in the highest incidence and severity of OM, followed by BU and CY/TBI regimens.²⁷ In a longitudinal study of 59 patients undergoing allogeneic HSCT, 76% developed oral ulcerations. Ulceration appeared 5 days after the HSC infusion and persisted for 6 days. OM resolved after the fifteenth day in 90% of the cases and this occurred concomitantly with a rise in the absolute neutrophil count to above 500 per l.²⁸ It has been reported recently that the non-myeloablative conditioning regimens given prior to allogeneic HSCT are associated with a low incidence of mucosal injury and related pain.²⁹

Patients who undergo allogeneic HSCT may also experience pain associated with acute GVHD-induced mucosal damage, which has a similar appearance to that caused by cytotoxic drugs.^{5, 22, 30} However, the typical clinical signs and symptoms of acute GVHD develop in many tissues.

Urinary bladder irritation, sometimes evidenced by bloody urine or painful urination, may occur following conditioning regimens that include CY or ifosfamide. Severe haemorrhagic cystitis (HC) is one of the most troublesome complications of allogeneic HSCT, causing significant morbidity, and it is sometimes life threatening. It is an early complication (developing within 30 days after HSCT) and is probably associated with the administration of CY, and/or use of TBI, and the coexistence of adenovirus or polyomavirus infection. The presence of acute GVHD may increase the risk of developing this complication.³¹

Pain in patients undergoing allogeneic HSCT may arise due to a variety of other causes. Cytotoxic drug-induced damage to the endothelium of the hepatic sinusoids may cause a hepatic veno-occlusive disease (VOD), in 10–60% of allogeneic transplant patients. This syndrome is characterized by hepatomegaly and right upper quadrant pain due to distension of Glisson's capsule.³² In the post transplant period, pain syndromes, such as bone pain, myalgia, headaches and neuropathic pain, have been reported and have been attributed to the administration of CYA³³ and/or G-CSF.³⁴ In addition, BM necrosis, a rare but dramatic and very painful complication, has been described in patients undergoing allogeneic HSCT following G-CSF administration³⁵ or due to acute GVHD.³⁶

Lastly, other painful complications have been observed during the transplant phase; they may be associated with bacterial pneumonia, abscesses, cellulitis and abdominal infections.³⁷ In particular, the oral, cutaneous and visceral manifestations of herpetic virus infections have a distinct pattern of disease development and may give rise to severe pain.^{38, 39, 40, 41}

Pain syndromes associated with late post transplant complications

In allogeneic HSCT patients, pain may develop in chronic GVHD, especially when the mouth is involved.^{42, 43} Pain has been reported by 80–100% of such patients and is associated with the presence of angular cheilitis, xerostomia, atrophy of tongue papillae, the formation of macules (not unlike those seen in lichen planus), and painful ulcers on the tongue and the gums. Moreover, painful manifestations of GVHD may afflict other mucosal sites.^{44, 45} In addition, some chronic manifestations of GVHD may resemble a painful autoimmune disorder, such as fasciitis and polymyositis.⁴⁶

CYA may result in drug-induced neuropathy and long-term corticosteroid therapy may lead to osteopaenia and osteoporosis, all of which may be associated with chronic pain.^{47, 48}

Opportunistic infections associated with herpes zoster virus (HZV) infections and the potentially devastating post-herpetic neuralgia (PHN) may cause pain. Indeed, reactivation of HZV is a significant cause of morbidity in patients who undergo HSCT;³ it has been reported in 15–45% of patients who underwent autologous HSCT³⁹ and in 41–59% of patients who underwent allogeneic HSCT.⁴⁹

Pathophysiology of pain in the HSCT setting

Pain is categorized as being nociceptive (somatic and visceral) or neuropathic in origin (Table 1). Breakthrough pain (BTP) is the sudden appearance of transient acute pain, in patients who have reported that their level of analgesia was stable. It can occur during both voluntary and involuntary movements.⁵⁰

This classification gives a rational approach for understanding and treatment of pain in an HSCT setting.

Pain syndromes due to raised BM pressure by increasing haemopoiesis or skeletal lesions are examples of deep somatic pain. Pain arising from the bladder and from the upper and lower gastrointestinal tract is an example of visceral pain. The pain associated with drug neurotoxicity and that associated with HZV reactivation has the features of neuropathic pain. Patients with osteolysis, osteopaenia or osteoporosis may suffer from either a localized and sometimes radiating and continual pain at rest, or from incidental pain that is provoked by movements.

Oral pain associated with mucositis may be categorized as superficial somatic pain. Pain stimuli from the mouth are conveyed to the central nervous system by two types of primary afferent neurones. The first group, the A fibres, are myelinated and conduct with high velocity. The second group, the C-fibre afferents, are unmyelinated fibres and conduct more slowly. Pain conveyed by the C-fibres can be relieved by opioids. In contrast, pain that is evoked by oral movement and contact with food and beverages is conveyed along A fibres and cannot be relieved by the conventional analgesics.⁵¹

The symptoms of gastrointestinal mucositis are sometimes vague and are expressed as abdominal pain (visceral pain) and gastrointestinal hypermotility with diarrhoea. The symptoms usually start appearing on the third day following HSC infusion and are full blown from the seventh day, which coincides with the full clinical expression of OM.

The pain due to HC is visceral in origin and is often accompanied by haematuria, dysuria, straining and terminal dribbling. The painful hepatomegaly that accompanies hepatic veno-occlusive disease is categorized as deep somatic in origin. Lastly, infection-related pain may show several features of pain that range from mild nociceptive (somatic and visceral) pain to the most devastating neuropathic pain (Table 1).

Prevention of pain and pain management in an HSCT setting

Assessment of pain

The cornerstones of pain management in an HSCT setting are the recognition of pain, diagnosis of its underlying cause and assessment of its intensity.

The primary source for pain assessment is the patient's report, which is also the principal source for the evaluation, except in infants where behavioural observations are used.⁵²

The intensity of pain can be assessed using any of several available pain rating scales, such as the visual analogue pain rating scale, the verbal pain rating scale, the numerical pain scale or the Wong–Baker FACES pain rating scale, which is suitable for children, and some elderly or cognitively impaired adults.⁵³

Using a numerical pain rating scale, the score for mild pain is between 1 and 4, for moderate pain is between 5 and 6, and for severe pain is between 7 and 10. Pain with a score greater than 5 is considered substantial because it interferes with the quality of life and is an indicator of poor control of pain.⁵⁴

In general, pain should be assessed routinely in all HSCT patients about twice daily, together with the assessment of other vital signs.⁵² In pain-afflicted patients, the evaluation of pain intensity should be done at the moment when pain develops (baseline) and at regular intervals, according to the time of onset of the analgesic and the duration of activity of the specific agent. This is mandatory to establish analgesic efficacy. Thus, for example, during morphine titration for oral pain in patients suffering from OM, pain should be assessed about every 10–15 min until a reduction in intensity of at least 50% of the basal pain score is reached. Once a stable level of pain relief is achieved and the most efficacious analgesic regimen is established, the assessment of pain can be done at less frequent regular intervals of several hours (for example 6 h), according to the institutional monitoring protocol for other vital signs.

Pain management in the HSCT setting

Pain management in the HSCT setting should incorporate analgesic interventions and specific measures aimed at treating the underlying causes of pain. The initial analgesic treatment of pain should be adapted to its intensity, using different available agents. Thus, non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol alone can be used for the relief of mild pain, whereas partial mixed opiate receptor agonists and mild opioids, such as oxycodone, hydroxycodone codeine and tramadol are beneficial for relieving moderate pain; finally, the pure -opiate receptor agonists or strong opioids, such as morphine and fentanyl, are the drugs of choice for treating severe pain.^{2, 55} Adjuvant pain therapy using tricyclic antidepressant and anticonvulsant drugs can be incorporated into the analgesic regimen to augment analgesia. Pethidine-induced analgesia is no longer recommended because of its potential to cause seizures and dysphoria. The appropriate analgesic drug and its route of administration in an HSCT setting should be carefully selected because adverse drug effects such as concomitant severe neutropaenia, thrombocytopaenia, renal failure and liver impairment can develop.

For example, the administration of NSAIDs can result in the development of potentially life-threatening effects, including gastropathy, nephropathy and haemostatic defects. NSAIDs should not be administered to HSCT patients who are at high risk because of coexisting renal disease, peptic ulcers or bleeding disorders.

When opioids are used, the initial administration and titration of these agents should begin with short-acting compounds that can be given frequently to relieve pain and to determine the most efficacious dose. Morphine, administered either by careful dose titration using an oral high-concentration morphine solution in patients who can eat, or by intermittent bolus i.v. injection, is the analgesic of choice for the initial therapy of acute and chronic severe pain because of clinical experience, manageability and versatility. Upward oral titration using morphine can be stopped either when pain is relieved without the impairment of cognitive status or when intolerable adverse effects occur. For BTP, morphine, administered i.v. at 20% of the basal oral dose, has been proposed as an inexpensive, safe and effective option.⁵⁰

An optimal pain management programme should include careful monitoring of the patient and the prevention and the treatment of side effects.⁵⁶ Thus, when morphine is used, an antiemetic, such as 1.5 mg haloperidol given every 12 h, should be administered. Because of the high rate of constipation among patients who are given opioids for 3 days or more, a scheduled bowel regimen, such as senna+docusate, should be prescribed in patients who are able to eat.

The therapeutic use of opioids requires knowledge of the potency relative to morphine and the bioavailability of each individual drug following the selected route of administration. The i.v. administration of opioids is used to achieve analgesia quickly in patients who are experiencing rapidly escalating or otherwise uncontrolled pain. The opioid can be delivered either by a continuous infusion (CI), by a PCA device or by PCA combined with CI in selected circumstances, such as in patients with mucositis.^{57, 58}

Patient-controlled analgesia relies on a pump that is programmed to deliver boluses at a lockout time (for example 15 min) until significant pain relief occurs. The administration of a loading dose of the opioid is recommended before initiating PCA to achieve rapid analgesia and predict subsequent PCA needs (Table 2). Once adequate analgesia has been attained, the amount of opioid already administered to the patient over the preceding interval should be used to determine the final rate of delivery by CI.^{5, 55}

Table 2 - Factors to consider for PCA and its monitoring.

Full table

To prevent pain during diagnostic procedures, provision of pre-emptive analgesia or induction of sedation and short-duration unconsciousness can be used, either by giving a soluble benzodiazepine such as midazolam, a short-acting anaesthetic agent such as ketamine or propofol, or an oral mucosal patch or lozenge containing a short half-life formulation of fentanyl citrate.⁵⁹ At the time of marrow harvest, it has been reported that there were no significant differences in the pain experienced by donors during marrow harvest following the use of regional or general anaesthesia. Furthermore, regional anaesthesia was considered safer and more cost effective than general anaesthesia, although there were no differences in the duration of hospitalization.⁶⁰ The mild to moderate pain experienced by patients and donors treated with G-CSF can be controlled with paracetamol. Infrequently, bone pain can be severe enough to require the administration of more potent analgesics. HSC infusion-related pain is transient and generally well tolerated.

Despite its frequency and clinical significance, no standard approach to prevent or treat OM currently exists. Basic oral hygiene, periodic dental care and comprehensive patient education remain important components of care for each HSCT candidate. Therapeutic modalities to treat mucositis have been limited to the use of palliative rinses, barrier protectants, topical antimicrobials and ice, and none of these measures has proven to be consistently effective.⁶¹ The introduction of newly developed agents such as palifermin, which has been reported to reduce both the severity and the duration of sores and ulcers in the mouth, could herald a new era of targeted therapy of mucositis.^{5, 62} Although these above-mentioned measures are marginally effective, analgesic therapy can allow the resumption of feeding and reduce the duration of hospitalization.^{5, 22} To control the nociceptive pain component of oral pain associated with mucositis, the potential utility of local topical application of opioids, such as a mouthwash containing 2% morphine, has been proposed.⁶³ However, the mainstay of analgesic therapy for oral pain associated with OM is the parenteral administration of opioids. For this purpose, tramadol is useful in the control of mild to moderate pain. There are numerous reports advocating the use of i.v. administered morphine as first-line therapy to relieve severe oral pain, using PCA because dose reduction and a shorter duration of opioid therapy can be achieved when compared with CI.^{57, 58, 61} The use of transdermal (TD) delivery systems for fentanyl and buprenorphine is a route of administration that is potentially advantageous for patients whose analgesia has been stably maintained. No data exist on the use of TD buprenorphine in HSCT recipients. However, conflicting results of the use of TD fentanyl have been recently published^{64, 65, 66, 67} and, therefore, no firm recommendations can be given on the use of this medication in the HSCT setting.⁵ To control the incidental pain associated with mastication and swallowing, a useful measure is cessation of oral feeding and replacing it with total parental nutrition.

Specific measures aimed at treating the underlying causes of pain are essential in a comprehensive pain management programme and can contribute significantly to pain relief. The treatment of chronic GVHD relies on the use of a variety of immunosuppressive and immunomodulatory drugs and interventions that include mycophenolate, monoclonal antibodies, sirolimus, pentostatin and extracorporeal photopheresis, as well as corticosteroids.⁶⁸ Moreover, corticosteroids⁶⁹ and tacrolimus,⁷⁰ when locally applied, can provide some therapeutic benefit to patients with GVHD-related oral ulcers. To prevent the occurrence of gastrointestinal mucositis, a panel of experts has recently recommended the administration of sulphalazine to patients undergoing radiotherapy and of octreotide to reduce the frequency and the volume of diarrhoea.⁶¹

The management of HC consists of hyperhydratation, blood transfusions, transurethral catheter placement and the evacuation of blood clots, continuous bladder irrigation, urine alkalinization, and either systemic or local oestrogen and antiviral therapy such as intravesical instillation of cidofovir. Intravesical instillation of formalin appears to be effective and safe and can be considered early in severe HC to reduce the risk of morbidity and mortality.³¹

Pharmacological therapy with orally and i.v. administered bisphosphonates has been shown to prevent bone loss and increase bone mineral density in HSCT patients.⁷¹ In patients with fractures and osteonecrosis, orthopaedic surgery and arthroplasty may also be required.

To prevent the development of PHN in patients with HZV infection, early intervention, with the administration of antiviral agents, neuroactive agents such as gabapentin, or opioid analgesics such as oxycodone or tramadol, is required.⁷²

Management of pain in HSCT patients with renal and hepatic impairment

Special care must be taken in the management of pain in HSCT patients with impaired renal function. The safest drugs in this setting are alfentanil, buprenorphine, fentanyl, ketamine and paracetamol because none of these drugs delivers a high active metabolite load or have a prolonged clearance.

The use of other agents, such as amitriptyline, gabapentin, hydromorphone and tramadol, requires specific precautions, while morphine and oxycodone should be avoided whenever possible.^{73, 74} Lastly, pethidine should not be used in patients with chronic renal failure due to the risk of significant neurotoxicity.

The oral bioavailability of most analgesics and adjuvant pain drugs is increased and their clearance is reduced in patients with hepatic impairment. Therefore, they must be used with caution and, when they are used, close patient monitoring is required. Treatment with amitriptyline, carbamazepine or valproate should be avoided because of the risk of inducing fatal hepatic failure.⁷⁴

Pain management by non-pharmacological measures in the setting of HSCT

Although the use of analgesics is the main approach for treating pain associated with HSCT, non-pharmacological measures may be used to supplement the efficacy of analgesics. The results of several controlled trials have reported reduction in the intensity of pain in HSCT patients who received mental relaxation and imagery training⁷⁵ or who were hypnotized.⁷⁶

Conclusion

Although recent advances in the conditioning regimen have reduced the painful complications of HSCT, pain and its treatment remains a major issue in the global management of HSCT patients. Research aimed at elucidating the basic mechanisms of pain in an HSCT setting and optimizing the application of the currently available measures could improve treatment strategies to reduce the number and minimize the severity of adverse reactions. In particular, the real impact of palifermin on mucositis and acute GVHD remains to be established.⁷⁷ Furthermore, bisphosphonates seem to be able to prevent or treat bone loss accompanying chronic GVHD in children;⁷¹ therefore, well-designed studies aimed at investigating their use, especially in young adults, could be an area of future research. Another area requiring further research is investigation of the optimization of analgesic therapy in HSCT patients. Indeed, the usefulness of TD opioids in patients with mucositis warrants thorough investigation. In addition, the increasing use of PCA for these patients justifies further investigation to standardize its utilization. Lastly, the possible introduction of new patient-activated drug delivery devices, recently reported as an innovative and effective measure in the treatment of acute post-operative pain,⁷⁸ may enhance the current management of mucosal pain. However, the key elements of pain management in HSCT patients remain the competence of and the empathy provided by a multidisciplinary team working together to provide the best available means to effect pain relief in patients with this debilitating condition.

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