Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0973-1075.19182
Source of Support: None, Conflict of Interest: None
Cancer of the cervix uteri is a common cause of pain among women. On the physical realm, the cancer may cause somatic [soft tissue and bone], visceral and neuropathic pain [lumbosacral plexopathy]. Radiotherapy and chemotherapy may cause neuropathy too. Psychological, social and cultural factors modify the pain. Evaluation of the individual type of pain and a patient-centred approach are fundamental requirements for rational management. Disease modifying treatment like radiotherapy and chemotherapy must be considered when applicable. Pain control is usually achieved by the use of WHO three-step ladder, remembering that possible association of renal dysfunction would necessitate caution in the use of NSAIDs and opioids. Side effects must be anticipated, prevented when possible, and aggressively treated; nausea and vomiting may already be present, and constipation can worsen pain when there is a pelvic mass. Pain emergencies can be treated by quick titration with intravenous morphine bolus doses. Neuropathic pain may warrant the use of usual adjuvants, with particular reference to cortico-steroids and the NMDA antagonist, ketamine. In intractable pain, many neurolytic procedures are tried, but a solid evidence base to justify their use is lacking. Continuous epidural analgesia with local anaesthetic and opioid may be needed when drug therapy fails, and desperate situations may warrant interventions such as neurolysis. Such physical measures for pain relief must be combined with psychosocial support and adequate explanations to the patient and the family.
Keywords: cancer cervix uteri, pain, palliative care, India, developing countries
Pain has always been a part of women's health experiences, inherent to such physiologic processes as menstrual cramping, labour contractions, and uniquely female illnesses, such as cervical or ovarian cancer. The origin of the pain is often in the physical realm, but it is manifested through an array of psychological, social, and cultural factors.
The classical well-recognised features of recurrent cervical carcinoma are the result of pelvic mass and lymphadenopathy. More recently, intensive pelvic radiation therapy and longer survival seem to have resulted in a greater incidence of peritoneal carcinomatosis, solid organ metastases or bony metastases. This has led to increased detection of less typical manifestations.
Pelvic cancer causes visceral, neuropathic, and somatic pains.
Somatic pain is due to stimulation of nociceptors in the integument and supporting structures, namely, striated muscles, joints, periosteum, bones, and nerve trunks by direct extension through fascial planes and lymphatic spread.
The cause for visceral pain could be spasm of the smooth muscles of hollow viscus, distention of the capsule of solid organs, inflammation, chemical irritation, traction or twisting of mesentery, ischemia and necrosis, or tumour encroachment of the pelvis and presacral regions.
In more than 60% of patients with malignant disease of the pelvic organs invasion of the nerve trunks and sacrum result in neuropathic pain. This can cause symptomatic sensory loss, causalgia, and deafferentation. Saphner and colleagues found in a study of 2261 patients that lumbosacral plexopathy caused by retroperitoneal lymph node metastases is the most common neurologic complication in patients with advanced cervical cancer.
Radiation and chemotherapy related neurotoxicity
In previously treated patients, the main differential diagnosis for neuropathic type of pain is radiation induced plexopathy. Radiation induced pain rarely develops within less than a year after therapy; the latency period can be several years. A clinical course with sensorimotor symptoms and signs progressing over months, electromyographic recording of myokymic discharges, and the absence of a space-occupying mass suggest late-onset radiation-induced plexopathy.Some chemotherapeutic agents may cause peripheral neurotoxicity and associated acute and chronic peripheral neuropathies, particularly if given to patients with preexisting hereditary or acquired neuropathies.,,
Bone metastasis in cervical carcinoma is a late manifestation of advanced malignancy. Atypical location of pain should alert the physician to suspect distant metastasis., The prevalence of osseous metastases in the setting of recurrent cervical carcinoma ranges from 15% to 29% as reported in multiple autopsy series., The vertebral bodies are by far the most frequently involved bones, followed by the pelvis, ribs, and extremities. ,  The most common mechanism of bone involvement is by the direct extension of neoplasm from para-aortic nodes into the adjacent vertebral bodies.
Psychosocial aspects of pain
A person with cancer faces many difficult issues- death, disfigurement, disability, dependence and disruption of relationships. In addition, cancers of the cervix raise issues like sexuality, femininity and social isolation., ,  In a study of patients with cervical cancers in India, sexual dysfunction was a major concern and concern about body image an important cause of distress among rural women.
Acknowledgement and understanding of the symbiotic relationship between physical and social pain reveals new perspectives on issues surrounding social support and neurochemical intervention in pain. The experience of physical pain has been shown to activate the same neural mechanisms as the experience of social separation or rejection. Social support, a sense of control and empowerment, and planning are all vital determinants of an individual's experience of pain.
Evaluation of patients with chronic pelvic pain is complex. A detailed medical history should be supplemented by psychological evaluation and assessment of the woman's social background.
Failure to assess pain is a critical factor leading to under-treatment. Assessment should occur:
•at regular intervals after initiation of treatment.
•at each new report of pain.
•at a suitable interval after pharmacologic or nonpharmacologic intervention, e.g., 15 to 30 minutes after parenteral drug therapy and 24-48 hours after oral administration.
Identifying the etiology of pain is essential to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes.
The goal of the initial assessment of pain is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient's ability to function.
The following are essential to the initial assessment:
A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation [hypoesthesia, hyperesthesia, hyperpathia, allodynia] in a painful area are suggestive of neuropathic pain. Physical findings of tumour growth and metastasis are also important to identify.
The cardinal clinical feature is severe, unrelentless pain. The local pain is pressure-like or aching in quality. The referred pain varies with the site of plexus involvement and can be burning, cramping or lancinating. A "hot and dry foot" syndrome may result from lumbosacral plexopathy and may reflect sympathetic fibre dysfunction.
Lumbosacral plexopathy may cause different clinical symptoms depending on the level of nerve involvement.
Infiltration of the upper plexus occurs in approximately one-third of patients. They present with pain in the back, lower abdomen, flank, iliac crest or antero-lateral thigh. This syndrome has associated neurologic deficits of L1 to L4 distribution.
Involvement of the lower plexus occurs in approximately one-half of patients, and these present with pain in the buttocks and perineum, with referral to the postero-lateral thigh. Examination may reveal associated L4 to S1 neurologic deficits, leg edema, and bowel or bladder dysfunction.
Sacral plexopathy can signal direct bony extension of a bony sacral lesion or a pre-sacral mass. Numbness of the dorsal medial foot and sole with associated weakness of knee flexion, ankle dorsiflexion and inversion is typical of lumbosacral trunk extension.
Sensory symptoms of numbness and paresthesia, as well as weakness and leg edema, usually develop weeks to months after pain begins.
Continual assessment of cancer pain is crucial. Changes in pain pattern or the development of new pain should trigger diagnostic evaluation and modification of the treatment plan. Persistent pain indicates the need to consider other aetiologies [e.g. related to disease progression or treatment] and alternative [perhaps more invasive] treatments.
Assessment of visceral pain
Most visceral pain is poorly localized. This makes visceral pain difficult to diagnose. For reasons that may be difficult to elucidate, the pain can be episodic, and this may make it difficult to distinguish between colicky pain and other nociceptive pain. A diagnostic-cum-therapeutic trial with an antispasmodic may become necessary and absence of response to the antispasmodic may have to be taken as a rather weak proof of absence of an element of colic. A more powerful antispasmodic like hyoscine butylbromide may sometimes work when dicyclomine has failed.
In the context of advanced incurable disease, clinical evaluation as described above is the mainstay of management. However, particularly when the cause of the pain is difficult to elucidate and when that makes it difficult to treat, radio-imaging may become necessary. Bone scan with radio-isotopes is the most sensitive for detection of distant bony metastases, while magnetic resonance imaging [MRI] may be most valuable when nerve compression is suspected or when there is combined bony and soft tissue involvement.
Cancer pain can be managed effectively in about 80-90% of patients through relatively simple means such as the appropriate use of the World Health Organization [WHO] analgesic ladder. Patients with advanced cancer cervix experience multiple concurrent symptoms with pain; therefore, optimal pain management necessitates a systematic symptom assessment and appropriate management for optimal quality of life.
Pain of different types is managed by different modalities depending on the age of the patient, the expected life expectancy, availability of invasive and non-invasive pain control modalities, and the resources of the patient, community, and health care agencies.
The recommended clinical approach outlined below emphasizes a focus on patient involvement.
1.Ask about pain regularly. Assess pain and associated symptoms systematically using brief assessment tools. Assessment should include discussion about common symptoms experienced by patients and how each symptom will be treated.
2.Believe patient and family reports of pain and of what relieves the pain. Choose pain-control options appropriate for the patient, family, and setting.
3.Empower patients and their families. Enable patients to control their course of treatment as much as possible. Discuss pain and its management with patients and their families.
4.Consider the cost of proposed drugs and the interventional procedures planned.
5.Prophylactic anti-constipation measures should be initiated in all patients before or during opioid administration in view of the fact that obstructive features are common in patients with cancer cervix along with other causes of constipation.
6.Judiciously use of medications in view of compromised renal function seen quite commonly in patients with advanced cancer cervix.
7.It is essential to provide adequate psychosocial evaluation and support.
8.Share documented pain assessment and management with other clinicians treating the patient.
The basic principles of pain mangement in cancer cervix are the following:
The oral route is preferred as long as a patient is able to swallow and as long as there is no significant intestinal obstruction. Each analgesic regimen should be adjusted for each patient's individual circumstances and physical condition.
By the clock
Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening. An as-needed rescue dose [breakthrough dose] should be combined with the regular fixed-schedule analgesics to control the episodic exacerbation of pain, often referred to as breakthrough pain.
Use of the WHO Ladder
The three step WHO analgesic ladder  is used bearing in mind the problems specific to the disease condition. If the pain is mild, as usual, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug [NSAID]. An NSAID may be of particular benefit in bone pain or when peritumour inflammation is contributing to the pain. Acetaminophen can be combined with aspirin and other NSAIDs to have additive analgesic efficacy, although it seems to lack significant peripheral anti-inflammatory activity in usual therapeutic doses.
NSAIDS should be administered with care in the elderly and those with compromised renal function. Similarly, the presence of bleeding tendency mandates the avoidance of traditional NSAIDs. It is also important to remember that while the COX-2 selective drugs are unlikely to cause platelet dysfunction, they offer no protection against renal dysfunction.
If pain persists or worsens despite appropriate dose of step1, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in those patients presenting at the onset with moderate-to-severe pain in favor of Step 2 or Step 3. Unfortunately, many patients with plexopathy or with distension type or colicky type of visceral pain may not respond well to oral opioids and may need the skilled use of adjuvants or alternate routes of administration of drugs such as epidural analgesia.
At each step of the ladder, an adjuvant drug or modality such as radiation therapy may be considered in selected patients.
Opioids, the major class of analgesics used in the management of moderate-to-severe pain, are usually effective, easily titratable, and have a favorable benefit-to-risk ratio.
Morphine is the most effective and commonly used opioid in cancer pain management, largely for reasons of economy, availability and familiarity.
Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when the pain intensity is highly variable.
Once stabilised, patients can be switched to a controlled-release or slow-release formulation which is more convenient and promotes compliance, provided it is easily affordable for the particular person.
1.Dose titration is largely patient-driven, as determined by the balance of analgesia with side effects. Opioid agonists of the step 3 type have no maximum dose or ceiling. The appropriate dose is the amount of opioid that controls pain with the fewest side effects. The goal is to achieve a favorable balance between analgesia and side effects through gradual adjustment of the dose.
2.The dose of immediate-release formulations can be increased on a daily basis if necessary, until pain relief is adequate. Among patients receiving relatively low doses of opioids, those with uncontrolled moderate-intensity pain require daily increases of between 25% and 50% to their previous dose, while patients with severe uncontrolled pain may require a higher increase. At higher opioid doses, increases of 20% to 30% would be more prudent. Rapid dose escalation requires close monitoring for both efficacy and side effects.
3.The rescue dose is generally calculated to be 15% to 20% or 1/6 to 1/5 of the total daily dose of the fixed schedule.
4.Occasionally, doses may need to be reduced or, rarely, stopped. This may occur when patients become pain free as a result of cancer treatment or treatments such as nerve blocks and radiation therapy. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended and usually adequate.
Palliative care services in India often see patients with poorly managed pain who come in agonizing pain. Oral opioid titration in such cases would not be quick enough. Intravenous titration of morphine has been successfully done and routinely practised in the Indian context., ,  This helps by achieving immediate pain relief, and also by serving as an index of opioid sensitivity of the pain. Once pain control is achieved, the patient is switched to oral opioid by the clock.
Clinicians should anticipate and monitor for side effects. The more common adverse effects include constipation, nausea and somnolence. These should be discussed with patients before starting opioids. Somnolence and nausea are more often encountered with initiation of opioid treatment but tend to resolve within a few days. Clinicians who follow patients during long-term opioid treatment should watch for potential side effects and manage them as the need arises.
It is essential to anticipate the constipating effects of opioids and to take preventive measures. Unlike nausea, complete tolerance to the constipating effect does not generally develop, and most patients require stimulant laxative/stool-softener therapy for as long as they take opioids. This particularly important for the patient with pelvic disease, in whom constipation can worsen pain as well as sub-acute intestinal obstruction.
Opioid-induced constipation is a frequent cause of chronic nausea and is said to occur in 40% to 70% of patients receiving opioids.
Nausea and vomiting
Nausea and vomiting occur in approximately one third to two thirds of patients taking opioids. However, the multicausal nature of the problem needs to be recognized since management is directed at identifying and addressing the various causes. Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting this adverse effect.
Cognitive and other neurotoxic side effects of opioids
Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized myoclonus, hyperalgesia and/or allodynia. Patients with renal impairment or those needing high doses of opioids are at greater risk of developing these side effects.
The aetiological contribution of opioids to cognitive impairment and delirium in the cancer patient is often difficult to determine, particularly in patients with advanced disease in whom the baseline vulnerability associated with multi-system impairment, and the concurrent administration of other psychotropic agents can complicate the assessment of etiology.
The general management approach to opioid-induced delirium requires a multidimensional assessment to determine the presence of other potentially treatable contributory factors such as dehydration, other centrally acting medications, sepsis, and hypercalcemia.
In addition to searching for underlying reversible causes of delirium, the symptomatic management of delirium requires the addition of a neuroleptic agent to control agitation and perceptual or delusional disturbance. Haloperidol is regarded as the drug of choice in this context and chlorpromazine is considered a useful alternative. Midazolam, a short-acting benzodiazepine given by continuous infusion, is sometimes necessary, especially in the case of nonreversible delirium. The specific management approach to opioid-induced cognitive and other neurotoxic side effects involves either a dose reduction, a change in route of administration, or an opioid-switch. If the pain is well controlled, and the cognitive and neurotoxic side effects are not severe, modest opioid dose reduction may be effective.
Adjuvant drugs are valuable during all phases of pain management to enhance analgesic efficacy, treat concurrent symptoms, and provide independent analgesia for specific types of pain. Since more than 60% of patients with cancer cervix and pain would have some element of plexopathy and because some neuropathic pains can be partially opioid-insensitive, adjuvant drugs have a definite role.
The usual adjuvant drugs used for neuropathic pain, such as the tricyclic antidepressants and anticonvulsants, are also used in patients with cancer cervix neuropathic pain syndromes. The analgesic benefits of tricyclic antidepressants have been well established and they are generally considered the first-line therapy for many neuropathic pain syndromes.
Corticosteroids have achieved wide acceptance in the management of patients with cancer pain. They are indicated as adjuvant analgesics for cancer pain of bone, visceral, and neuropathic origin. Much of the pain in cancer cervix has an inflammatory component in its causation and hence corticosteroids have a particular role to play. Dosage recommendations vary from a trial of low-dose therapy such as dexamethasone 1 to 2 mg or prednisolone 5 to 10 mg once or twice daily  to a starting dose of dexamethasone 10 mg twice daily with subsequent tapering to the minimal effective dose. Another suggested use of corticosteroids is in high doses for short periods in patients with severe pain. This empirical approach recommends a regime of a single bolus of dexamethasone 100 mg IV followed by a small amount given 4 times per day and then tapered over the next few weeks.
Although there is widespread acceptance of steroid therapy, mostly via the oral route but also subcutaneously and intravenously, data remain inadequate for definitive conclusions regarding efficacy and dosing guidelines., , 
There is increasing evidence for the importance of NMDA receptors in refractory cancer pain. Many pain syndromes in cancer cervix are difficult to treat and become refractory to regular management. Ketamine in subanaesthetic doses has been used in this setting. It has been suggested that oral ketamine may be a more potent analgesic and have a more favorable side-effect profile than parenteral ketamine. Doses as small as 0.2 mg/Kg Q 6-8 H are commonly recommended; but sometimes beneficial effect is obtained with higher doses of about 0.5 mg/Kg q6H or more. The severe psychomimetic adverse effects associated with this treatment, including vivid hallucinations, limit the widespread use of ketamine, especially in the higher dosage range. Co-administration of a neuroleptic or benzodiazepine is recommended to limit the emergence of these effects. A systematic review of the benefits and harms of ketamine in managing cancer pain revealed a general lack of studies and small subject numbers  precluding a definitive conclusion on benefits and harms.
Pain clinics often undertake interventional procedures in the management of intractable pain from cancer of the cervix. A review of some basic anatomic facts are necessary for understanding their relevance.
Innervation of the uterus and the cervix
•The nerves of the uterus arise from the inferior hypogastric plexus, largely from the anterior and intermediate part known as the uterovaginal plexus. This lies in the broad ligament on each side of the cervix. Nociceptive impulses from the body of the uterus are transmitted through the T11 and T12 nerves and those from the cervix and lower uterine segment through the pelvic nerves to the S2, S3 and S4 spinal segments.
•Parasympathetic fibres are from the pelvic splanchnic nerves [S2-4], and sympathetic fibres are from the above plexus. The autonomic fibres of the uterovaginal plexus are mainly vasomotor.
Neurolytic sympathetic plexus block has been proposed to prevent the development of pain and improve the quality of life of patients with cancer, thus NSPB for the management of cancer pain is considered earlier in the disease by some.
Bilateral percutaneous neurolytic superior hypogastric plexus block has been suggested as a possible means for providing palliation of pain in gynecologic cancer. Although it requires radiologic imaging, the procedure is relatively undemanding of the experienced pain specialist. Some consider the risk: benefit ratio to be uniquely favorable and recommend that NSPB should be considered early in the treatment of abdominopelvic pain that is expected to persist, especially for pain not adequately responsive to conventional drug therapy.
However, there is very little evidence base for the use of neurolysis in pain of cervical cancer and this procedure does not have wide acceptance, unlike the use of celiac plexus block in upper abdominal cancer. Neural blockade is not a panacea for cervical cancer pain as multiple pain mechanisms are often involved and because progression of disease can change the underlying pain mechanisms. Careful assessment is required to elicit the need for complementary interventions, including pharmacological management and psychobehavioral and rehabilitative approaches, combined with attention to the palliation of other symptoms.
When routine drug therapy fails to achieve adequate pain relief, lumbar epidural catheterization and continued infusion of a local anaesthetic and an opioid is a viable option. The authors' usual practice is to start with 50 ml of 0.1% bupivacaine with 3 mg of morphine and to administer this at a concentration of 4 ml per hour. It is often necessary to titrate the concentrate and volume of infusion with pain relief. A usual rule is to titrate up the concentration of bupivacaine [at the risk of numbness and motor block with rising concentration] if there is inadequate quality of pain relief. If dermatomal coverage of pain is inadequate, the volume of infusion is titrated up to 6-8 ml per hour. The procedure carries the risk of urinary retention and can sometimes necessitate catheterization of the bladder. Delayed respiratory depression is a possibility with epidural morphine; but is unlikely to occur at the above dosage range. Pruritus occurs less often, and ondansetron would be the drug of choice to treat it. Long term epidural catheterization also has the disadvantage of catheter-related back pain or of sepsis. In addition, there is also the disadvantage of prolonged hospitalization, which in the Indian context is often impossible.
When an epidural works and when prolonged epidural catheterization becomes impossible, epidutal neurolysis is indeed a possible option, though it is not a commonly recommended procedure. This is undertaken only in the patient who is incontinent of bladder and bowel and has paraplegia, for fear of the procedure itself causing these problems. The authors have experience with this procedure in two such patients with pelvic pain [though not caused by cancer of the cervix]. For this, we modified and used the technique described by Korevaar. The results were good in these two patients with no adverse consequences.
Adequate psychosocial support is an integral part of successful pain management in cancer cervix. The support received from caregivers, the quality of the relationship between individual and caregiver, personal expectations, and an individual's sense of control and empowerment are all factors that play an important role in effective pain control., 
Patients and the family members may have difficulty remembering details of the pain management plan. Therefore both oral and written information and instructions should be provided about pain, pain assessment, the use of drugs and other methods for pain relief as part of the treatment plan. Patient education should emphasize that almost all pain can be effectively managed. Major barriers to effective pain management should be discussed to correct any misconceptions.
In our resource-poor country, delayed and inadequate treatment, lack of facilities for investigations, poverty and the poor status of women in society contribute to a high prevalence of unalleviated pain from cancer of the cervix. The disease process can be associated with several types of pain that are difficult to control including lumbosacral plexopathy, visceral pain and bony pain. Psychosocial problems worsen the pain experience. Proper evaluation of the type of pain and suitable adaptation of the WHO analgesic ladder are keys to successful management. Corticosteroids have a significant part to play in the treatment of pain. In difficult situations, oral ketamine may have a role. The judicious use of invasive procedures including epidural analgesia and neurolysis may have a role in selected cases.