Pain Management in Gynecologic Cancer

Pain associated with gynecologic cancer can be severe, may limit potentially curative treatment of the malignancy, and often impairs quality of life. The majority of patients can obtain relief through the use of available analgesic therapies. A thorough pain history and physical assessment are critical in determining the pain syndromes involved and selecting the most appropriate analgesic agents. When standard pharmacologic therapies are ineffective or produce unacceptable, unmanageable adverse effects, interventional techniques are warranted. Physicians and others caring for these patients must be aware of common concomitant emotional and physical symptoms as well as management techniques and available resources.

Few prevalence studies have been conducted specific to gynecologic malignancies and pain, with an estimated wide-ranging prevalence of 40% to 100% in those with uterine, cervical, or ovarian cancers.¹ When all persons with cancer are considered, pain is experienced by approximately one third of those receiving treatment and two thirds or more of those with advanced disease.^2,3 Unfortunately, poor pain control persists, with several risk factors identified for unrelieved pain. In a study of 1308 outpatients with metastatic cancer treated at oncology centers affiliated with the Eastern Cooperative Oncology Group (ECOG), 67% had experienced pain during the week preceding the interview and 36% had pain significant enough to decrease functioning. Using accepted guidelines for cancer pain management to determine whether analgesic regimens were appropriate, 42% of these outpatients studied received inadequate analgesic therapy.⁴ Predictors of poor pain control included discrepancies between the physician’s and the patient’s assessment of pain intensity and the presence of pain that was perceived by the physician to be unrelated to the cancer. Minorities, the elderly, females, and those with better performance levels were individuals at risk for poor pain relief. More recent studies have confirmed that minority patients do not receive adequate pain control.⁵

The barriers to adequate control include those related to health care professionals, the patients, their families, and the health care system.^6,7 Health care professionals often receive inadequate training in pain control. Compounding this is the low priority placed on pain assessment and its treatment. Additionally, fear of regulatory scrutiny and concerns about causing addiction lead to inadequate prescribing of opioids. Patients and family members also are anxious about addiction, leading to undermedication even when the amount ordered is adequate. Furthermore, patients may not realize that pain is subjective, not observed physically or in laboratory values, may assume the professional is aware of their discomfort, and may neglect to report their pain. Finally, the system presents obstacles through the lack of availability of opioids because pharmacies are hesitant to carry these drugs. Moreover, the high cost of analgesics limits their use in some situations.

Pain syndromes commonly seen in gynecologic cancers can result from three primary etiologies. The majority of pain experienced by individuals with cancer originates directly from the tumor.^{8, 9} Pain can also occur as a result of therapy aimed at reducing the tumor, including surgery, chemotherapy, radiation therapy, and hormonal therapy.^{10, 11} Finally, people with cancer can develop pain totally unrelated to the cancer or its treatment. Table 1 lists common pain syndromes seen in gynecologic malignancies.

Table 1. Pain Syndromes Common in Gynecologic Malignancies

  Pain Syndromes Related to the Cancer
  Ascites
  Acute abdomen
  Adnexal torsion due to ovarian cancer
  Bone metastases
  Bowel obstruction
  Fistula formation and skin maceration (also due to treatment)
  Fungating tumor
  Herpes zoster/postherpetic neuropathy (may also be due to immunosupression resulting from  cancer treatment)
  Infection
  Lumbosacral plexopathy
  Lymphedema (may be due to radiotherapy)
  Pudendal neuropathy secondary to sacral involvement by tumor

  Pain Syndromes Related to the Treatment
  Chemotherapy-induced peripheral neuropathies
  Taxanes, particularly in combination with cisplatin or carboplatin
  Abdominal pain due to intraperitoneal chemotherapy
  Corticosteroid-induced muscle and joint pain/aseptic necrosis of bone
  Hormonal therapy–induced fluid retention
  Radiation-induced pelvic pain and pelvic insufficiency fractures
  Postradiation cystitis
  Postradiation proctitis

  Pain Syndromes Unrelated to Cancer or Its Treatment
  Arthritis
  Migraine

The diagnosis of pain begins with an extensive history, including medications, and continues with a comprehensive physical examination.⁹ Ancillary diagnostic tests may be indicated in some circumstances, depending on the goals of care.

Pain History

Patients should be asked about the location of pain or, in many cases, the multiple sites of pain that may exist. For example, women with advanced ovarian cancer may have neuropathic pain secondary to the chemotherapeutic regimen, along with visceral pain associated with ascites or increasing tumor burden. The location of pain may be in a stocking or glove distribution, as seen in chemotherapy-induced peripheral neuropathy, or along a single dermatome as a result of postherpetic neuropathy. Pain can also be referred, so that liver metastases, normally associated with right upper quadrant pain, can produce pain in the back or shoulder. Additionally, tumor pressing against the diaphragm can be perceived as pain in the right shoulder.

The severity, or intensity, of the pain should be quantified using a standard measure such as a numeric rating scale.¹² The patient is asked to rate the pain on a 0 to 10 scale, where 0 indicates no pain and 10 indicates the worst pain imaginable. Although the results may be highly variable between similar patients, the purpose of such quantification is to gauge the efficacy of treatments. Does the intensity diminish with the addition of an analgesic? Another strategy to capture this information is asking the patient to quantify the amount of pain relief derived from a treatment using a 0% (no relief) to 100% (complete relief) scale.

The history should also include questions regarding the quality of pain. There are two broad categories of pain, nociceptive and neuropathic. Nociceptive pain is typically described by patients as “aching” or “throbbing” and is generally associated with musculoskeletal or soft tissue damage. Visceral pain, common in advanced gynecologic malignancies, is often included in this category and may be described as “cramping.” Neuropathic pain is generally associated with damage to the peripheral or central nervous system. Patients often use terms such as “burning,” “tingling,” “electrical,” “stabbing,” or “pins and needles” to describe neuropathic pain. They may describe tactile allodynia, pain as a result of light touch, and hypesthesia in the affected area. The location of the pain is critical in determining the underlying etiology. This information is directly linked to the analgesic regimen because neuropathic pain typically requires the use of adjuvant analgesics.

Pain may have a temporal pattern, worsening at different times during the day or night, and is often exacerbated by activity, such as movement or walking. Patients should be questioned about these variations in the pattern of pain. Many patients have continuous pain, with periods of intense episodes, referred to as breakthrough pain. An example of this phenomenon would be continuous visceral pain owing to tumor burden with exacerbations after eating owing to a partial obstruction.

Particularly with lower extremity neuropathies, patients should be queried regarding changes in gait, including frequent falls, because this may be a result of decreased sensation and motor weakness. Another indicator of decreased sensation associated with neuropathy is the report of frequent bruises in the affected region. Furthermore, questions regarding bowel function and sexual activity reveal potential autonomic nervous system dysfunction common in some chemotherapy-induced neuropathies, a complication of surgery or radiotherapy (alone or in combination), or a direct result of the tumor.

Medication History

A complete medication history is essential, with particular attention to analgesics. This includes determining what has been ordered for pain, what the patient is actually taking, and why any disparity between the two exists. Patients may withhold medication owing to fears, lack of efficacy, adverse effects, or cost. In addition to the medications ordered by the physician, patients may be taking over-the-counter drugs and herbal remedies. Evaluate the total acetaminophen content of both ordered (particularly combination opioids such as codeine or hydrocodone admixtures) and over-the-counter drugs; the recommended daily maximum dose is approximately 4000 mg in persons with a functioning liver.¹³ Patients should also be questioned regarding their past and current use of recreational drugs and alcohol. Patients with a past history may be particularly reluctant to take opioids. Patients with a current history of abuse present more complex challenges.¹⁴ Psychologists, substance abuse experts, and others may be consulted when developing a plan of care. Throughout the course of the pain history, it is useful to determine the meaning of pain for that patient and their family members. Pain may be perceived as a punishment, and reframing is needed to provide comfort. Chaplain or social work support is indicated. Consider cultural effects on the individual’s pain perception and implications for the plan of care.

Physical Examination

A comprehensive physical evaluation is crucial, including observation (e.g. erythema in the calf may be cellulitis or deep vein thrombosis), auscultation (e.g. high-pitched bowel sounds in obstruction), palpation (e.g. differentiating masses from impacted stool), and percussion (e.g. establishing fluid or air levels).¹⁵ Particular attention is given to the neurologic examination, including the sensory, motor, and autonomic systems. In general, the distribution of neuropathic pain follows a nerve, plexus, root, or the cord, whereas nociceptive pain is less specific in its location.

Sensory evaluation can differentiate large fiber versus small fiber damage.^{16, 17} Reduced sensation to vibration or altered ability to sense proprioception suggests large neuronal fiber damage. Changes in temperature sensation in the affected region and altered response to pin prick are common indicators of small fiber dysfunction. For example, cisplatin is known to produce large fiber damage, whereas paclitaxel produces changes in both large and small neuronal fibers, with greater injury to the small fibers. Changes to the chemotherapeutic regimen, including dose alterations, may be indicated. Concomitant disorders can also produce neuronal injury, such as vitamin B₁₂ deficiency leading to large fiber damage. Supplementation might be indicated in patients with such deficiencies.

The evaluation of tactile allodynia includes lightly stroking the area with a brush or cotton ball. Holding a cool or warm item lightly against the skin tests thermal allodynia. Reflexes are tested, particularly in the affected areas, and are often found to be reduced or absent. Standard motor evaluation should include observation of gait as well as assessment of strength and tone. The primary purpose of the history and physical examination is to establish the diagnosis, rule out potentially treatable causes, and establish a baseline on which to gauge the efficacy of analgesic therapy.

Radiographic studies and laboratory analyses can contribute essential information to the pain assessment. For example, bone scans can identify the presence of metastases causing pain. In this circumstance, radiation therapy may be warranted. Tumor markers, such as CA-125, may provide evidence for advancing disease. Moreover, laboratory data may reveal other abnormalities that can complicate pain therapy, including calcium levels to rule out hypercalcemia as a cause of confusion in patients receiving opioids. The degree of the diagnostic evaluation is based on the course of the patient’s illness as well as the goals for care. Patients with advanced disease who are no longer considering curative therapy may wish to forgo extensive workup and have their pain treated empirically.

The goals of pain management in gynecologic malignancies include relief of pain, prevention and alleviation of adverse effects of pain therapies, and enhancement of quality of life. A variety of pharmacologic therapies have been shown to be effective in relieving pain common in gynecologic malignancies: (1) nonopioids, including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; (2) opioids; and (3) adjunct drugs, such as antidepressants, anticonvulsants, corticosteroids, local anesthetics, and others. Reducing tumor bulk through the use of cancer therapies, including chemotherapy, radiation therapy, and in some cases, surgery, will be effective in many situations. Ablative procedures, such as nerve blocks and other invasive techniques, may be indicated in select cases. Nonpharmacologic approaches include cognitive-behavioral techniques and physical measures.

In general, when initiating pharmacologic therapy, only one drug should be started at a time and titrated slowly. Prescribing several drugs at one time precludes determination of the most effective agent or, if adverse effects occur, the agent responsible for complications. However, in clinical practice when patients may present in severe pain, several analgesic may be instituted to obtain the maximum effect.

Nonopioids

Nonopioids include NSAIDs and acetaminophen. NSAIDs interfere with the enzyme cyclooxygenase (prostaglandin synthetase), which blocks the conversion of arachidonic acid to prostaglandins (PGE₁), prostacyclins (PGI₂), and thromboxane (TXA₂). Prostaglandins are known to sensitize tissues to the effects of inflammatory mediators such as bradykinin. Inhibition of prostaglandin synthesis leads to relief of inflammation and pain.¹⁸ In addition, these agents are antipyretic.

The toxicities associated with these agents can be significant, including gastrointestinal effects, ranging from dyspepsia to hemorrhage, prolonged bleeding time, renal dysfunction, and hypertension.^{19, 20} Risk factors include age, history of ulcer, concomitant use of corticosteroids or anticoagulants, and higher NSAID doses and may include cigarette and alcohol use.²¹ Prevention of gastrointestinal toxicity includes the administration of prostaglandin analogues, such as misoprostol, to replace the action of prostaglandin in the stomach. Other prophylactic measures include proton pump blockers. The prolonged bleeding times are reversible once the drug is cleared from the plasma, except for aspirin, which has an irreversible effect on platelet aggregation. Thus, aspirin may be discontinued approximately 1 week before planned invasive procedures to limit the potential complications associated with prolonged bleeding. In most cases, renal dysfunction is corrected once the NSAID is cleared from the plasma.²¹

Drug interactions can occur when administering NSAIDs in women with gynecologic cancers. Because NSAIDs are metabolized in the liver, altered hepatic function may modify NSAID bioavailability. Decreased hepatic function as a result of disease, chemotherapy, or radiotherapy will result in impaired NSAID metabolism, necessitating a reduction in dose. Furthermore, NSAIDs are excreted by the kidneys and may inhibit the renal tubular secretion of other compounds.

The new generation of NSAIDs, called cyclooxygenase-2 (COX-2) inhibitors, have efficacy approximately equal to that of traditional NSAIDs. Although COX-2 inhibitors were once considered safer than traditional NSAIDs, controversy exists regarding their safety and whether gastrointestinal toxicities are truly decreased.^{22, 23} Thus, cost-benefit ratios must be considered when choosing between traditional NSAIDs and COX-2 inhibitors.

Acetaminophen has both analgesic and antipyretic properties, with little anti-inflammatory activity. Because acetaminophen concentrates in the liver and, in large doses, (10 g) can lead to hepatic necrosis, maximum daily doses should not exceed 4 g or 4000 mg.¹³ This becomes a concern when administering admixtures of opioids and acetaminophen, particularly if patients are taking additional over-the-counter preparations containing acetaminophen.

Nonopioids used alone or in conjunction with adjuvant agents may provide sufficient relief of mild pain; however, as pain increases to become moderate or severe, opioids must be added to the treatment regimen.

Opioids

Opioids are the treatment of choice for a variety of pain syndromes common in gynecologic malignancies. They are safe, when used appropriately, and in the majority of cases, highly effective. Appropriate for moderate to severe cancer pain, several phenomena are associated with their use, and misunderstandings regarding these phenomena lead to significant undertreatment of pain. Tolerance is “a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.²⁴ Tolerance is easily overcome by increasing the dose of the opioid; because there is no maximum dose or ceiling effect of agonist opioids, this can be safely accomplished by careful titration. The dose necessary to relieve pain is highly variable and should be based on the patient’s self-report of pain severity. An example in gynecology oncology is the patient with ovarian cancer who has been taking opioids for pain relief and is now faced with a surgery for relief of obstruction. The dose needed after surgery will be significantly higher, owing to tolerance, when compared with an opioid naïve patient. Conversely, there is a growing awareness that the need for increasing doses of opioid in the person with any type of cancer is more likely a sign of disease progression or an effect of treatment, rather than the development of tolerance.

Physiologic dependence is “a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”²⁴ Opioid withdrawal signs include agitation, abdominal cramping and diarrhea, rhinorrhea, piloerection, and return of pain.²⁵ Physiologic dependence is not addiction, and should not be a clinical problem. If an opioid is no longer necessary and is to be withdrawn, for example after obtaining relief from radiation therapy or a neurolytic procedure, it should be done so gradually. Reduce the dose by 25% daily to prevent the abstinence syndrome.²⁵

A more common cause of the abstinence syndrome is the use of opioid antagonists (such as naloxone). These agents should be used cautiously, particularly in persons receiving chronic opioid therapy.Naloxone is not an innocuous drug, having been associated with hypertension, ventricular arrhythmias, pulmonary edema, and sudden death in healthy individuals.^{26, 27, 28} In those rare circumstances in which true respiratory depression occurs secondary to opioid administration, naloxone can be mixed in 10 mL of saline solution and administered slowly in 1-mL increments to antagonize the respiratory depressant effects without precipitating an acute episode of the abstinence syndrome.

Psychological dependence, or addiction, is “a primary, chronic, neurobiological disease with genetic, psychological, and environmental factors influencing its development and manifestations … characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm and craving.”²⁶ Fear of addiction is rarely justified and should not serve as a barrier to adequate cancer pain relief. Unfortunately, owing in part to excessive media attention to drug diversion, patients and family members fear the development of addiction due to the use of opioids. Education is warranted.

Opioid Selection

A wide variety of opioids is available for clinical use in various formulations, including immediate-release tablets, long-acting pills and capsules, liquids, suppositories, and parenteral solutions (Table 2). The choice of opioid is based on the patient’s previous response to a particular agent, including both efficacy and adverse effects, as well as the present or future need for alternate routes of delivery. Opioids work to relieve a wide variety of pain syndromes, including both nociceptive and neuropathic pain. Formerly referred to as “opioid-nonresponsive pain,” analysis of existing studies suggests that opioids are effective in relieving neuropathic pain.²⁹ In general, higher doses of opioids are needed. Scheduled dosing is preferred over as-needed administration, beginning with a low dose and gradually titrating upward. Failure to respond to one opioid should result in rotation to another, owing to the wide variability in response to individual opioid agonists.

Table 2. Opioid Analgesics

IV, intravenous; PO, by mouth; SQ, subcutaneous.
^* Acetaminophen-opioid admixture: maintain 4000 mg/day in patients with normal liver function.
^†See Table 3 for information regarding methadone equivalencies.

Several agents should be avoided in chronic cancer pain management. Meperidine is metabolized in the liver to normeperidine, which is then excreted through the urinary system. Excretion is altered in those individuals with renal dysfunction, leading to accumulation of normeperidine, and resulting in central nervous system toxicity such as seizures.^{30, 31} Meperidine has poor oral bioavailability; 50 mg of oral meperidine is approximately equianalgesic to two aspirin tablets (650 mg). Propoxyphene, which is metabolized to norpropoxyphene, also should be avoided owing to the potential for central nervous system toxicity and its overall poor analgesic effect. Mixed agonist-antagonists, such as butorphanol, produce psychotomimetic effects and a ceiling dose, making these agents of limited, if any, value in cancer pain control.

Although long considered the gold standard, recent evidence suggests that morphine metabolites may accumulate in the face of renal dysfunction. Morphine-3-glucuronide and morphine-6-glucuronide may lead to myoclonus, hyperalgesia, nausea and vomiting, and sedation.³² Opioid switching is recommended if these effects occur or when significant renal impairment develops. Alternate agents include hydromorphone, fentanyl, and methadone if parenteral routes are necessary; alternate oral agents include hydrocodone, hydromorphone,  oxycodone, and oxymorphone. Transdermal fentanyl is an additional option when considering alternatives to morphine.

Methadone has unique properties that may promote its use in cancer pain management, particularly in neuropathic pain. In addition to opioid receptor binding, methadone may also antagonize the N-methyl-d-aspartate (NMDA) system. Methadone can usually be given every 8 hours owing to its long half-life, providing longer relief and allowing most patients the ability to sleep through the night. An additional benefit is the low cost of methadone, an essential attribute because cost can be a significant barrier. Conversion from one opioid to methadone can be complex because the equianalgesic dose of methadone varies based on the patient’s previous dose of opioid. The ratio is approximately 1:1 in acute pain, but when existing doses of morphine are higher, for example more than 300 mg/day, the ratio may be 20 mg morphine:1 mg methadone (Table 3). Conversion and titration should occur very gradually, over 7 days or longer, to prevent excessive sedation or other untoward events.³³

Table 3. Methadone Equianalgesic Dosing

Opioid-Related Adverse Effects

Opioid-related adverse effects can be managed and, in some cases, prevented. Constipation occurs as a result of binding to opioid receptors distributed throughout the gastrointestinal tract, leading to several alterations in function: peristalsis is delayed and resorption of water from fecal contents into the colon is increased.³⁴ The result of these changes is constipation, which in most cases can be prevented with stool softeners in combination with stimulant laxatives. Tolerance does not develop to these effects of opioids; therefore, a bowel program must be continued during opioid therapy and increased when opioid doses are titrated upward.

Respiratory depression due to opioid administration is greatly feared, yet the incidence of this adverse effect is quite small and is exceptionally rare in persons tolerant to the opioid. In the majority of cases, sedation precedes respiratory depression, providing an obvious early warning sign. Nausea and vomiting are known effects of opioid administration, particularly during initial exposure to the drug; approximately 40% of postoperative patients given opioids will vomit. Antiemetics given continuously during the first 24–48 hours of opioid therapy will often relieve these effects. In those rare persons who continue to experience nausea and vomiting, changing to a different opioid may provide relief. Particularly in women at risk for obstruction due to gynecologic cancers, other causes of nausea and vomiting should also be considered.

Sedation and diminished concentration can occur when opioids are initially introduced, but tolerance to this effect generally builds rapidly. If the effect persists, the dose of opioid may be reduced and the frequency of administration increased. Switching to an alternate opioid may be useful. In addition, psychostimulants, such as methylphenidate, 2.5–10 mg in the morning and in the early afternoon, may provide relief.³⁵ To avoid sleep deprivation during the night, doses of the psychostimulant should not be repeated in the late afternoon or evening.

Pruritus and urinary retention are less common and are usually seen with spinal drug delivery. Tolerance generally develops to these effects within several days after initial exposure to the opioid. Dizziness can be seen with tramadol, particularly in elderly patients.³⁶ Myoclonic jerking is a known effect of high-dose opioids, although particularly sensitive individuals may experience this at lower doses. This may also be related to accumulation of morphine metabolites. The opioid can be switched, or clonazepam, beginning at doses of 0.5 mg orally twice daily and titrated upward, can be given to reduce this effect. Hallucinations can occur but are rare, and are more often due to delirium related to other organic disorders. Sexual dysfunction as a result of chronic opioid use, including amenorrhea and reduced libido, has been reported.^{37, 38}

Routes of Administration

Although most cancer patients can attain adequate pain relief using oral analgesics, even at the end of life, occasionally, alternative routes, including rectal, sublingual, buccal, transdermal, or parenteral administration, may be required (Table 4). Obstruction is a common phenomenon in gynecologic cancers that may require the use of routes other than oral delivery. Numerous commercial forms of these preparations are available. In addition, pharmacists can often compound solutions, suppositories, and other formulations. However, intramuscular injection is not recommended, owing to variability in uptake of the drug and pain on administration.

  Table 4. Routes of Opioid Administration

  Enteral
  Oral
  Transmucosal
  Buccal
  Sublingual
  Rectal
  Stomal
  Vaginal
  Parenteral
  Subcutaneous
  Intramuscular (Not Recommended)
  Intravenous
  Spinal/Central Nervous System
  Epidural
  Intrathecal
  Intraventricular
  Others
  Transdermal
  Iontophoretic
  Nasal
  Inhalational

Opioid Rotation

When the treatment of opioid-induced adverse effects is not successful, changing to an alternative opioid, also called opioid rotation or switching, can be useful. Convert the daily dose of the current opioid, such as morphine, to the equivalent dose of an alternate opioid, such as hydromorphone, using equianalgesic tables as a guide. The 24-hour equianalgesic dose is usually reduced by approximately 20–25% owing to incomplete cross-tolerance and is titrated as needed.³⁹ Ongoing evaluation of the efficacy of any analgesic regimen is essential, and doses of drug must be titrated based on the patient’s self-report of pain.

Long-Acting Formulations

Long-acting or sustained-release oral opioid preparations allow convenience and improved quality of life. Several formulations are currently available in the United States, including once-a-day morphine, twice-daily morphine, twice-daily oxycodone, twice daily oxymorphone and transdermal fentanyl.⁴⁰ Methadone is often included in this list because it can be given every 8 hours. Long-acting hydromorphone is available in Canada and Europe, and may soon be released in the United States. When using these sustained-release oral formulations, as well as transdermal fentanyl, several principles should be considered: (1) titrate with a short-acting product, such as immediate-release morphine, oxycodone, or hydromorphone, then determine the dose that provided relief during a 24-hour period, and convert that dose to an equivalent sustained-release opioid; (2) immediate-release opioids should be available for breakthrough pain, with each dose calculated as approximately 5–20% of the 24-hour total sustained-release opioid; and (3) if the patient consistently requires more than two or three doses of breakthrough medication in a 24-hour period, the total breakthrough dose needed during that time should be added to the sustained-release dose. There is great variability in opioid requirements, such that the dose of opioid necessary to relieve pain is the correct dose for that individual. Although opioids are the mainstay of cancer pain treatment, other agents, referred to as adjuvant drugs, provide additional relief, particularly for neuropathic pain.

Adjuvant Agents

Originally released for other purposes, adjuvant agents have been found to be useful in the management of complex pain syndromes.

Corticosteroids

Although there are no randomized clinical trials, corticosteroids have long been used to treat a variety of neuropathic pain states, particularly those related to cancer. Dexamethasone has the least mineralocorticoid effect, and owing to the long duration of effect, dosing can be scheduled once per day.⁴¹ Typical doses range from 8 to 20 mg/day. Unfortunately, immunosuppressant and endocrine effects limit long-term use. Proximal muscle wasting occurs after 4–6 weeks of therapy.

Antidepressants

Tricyclic antidepressants block the reuptake of biogenic amines, including serotonin and norepinephrine.⁴² Although amitriptyline is studied more than other agents in this category, its anticholinergic effects may not be well tolerated, particularly in the elderly. Alternative agents, with fewer adverse effects, include nortriptyline or desipramine. Patients with pre-existing conduction abnormalities should have a baseline electrocardiogram because the tricyclic antidepressants can alter cardiac conduction. In all patients, a low dose should be started, usually at bedtime, and titrated every 3–7 days based on the patient’s response.  Serotonin selective reuptake inhibitors (SSRIs), such as fluoxetine, appear to have little efficacy in relieving neuropathic pain.⁴² Newer serotonin – norepinephrine reuptake inhibitors (SNRIs), including venlafaxine and duloxetine, have been shown to be effective in neuropathic pain.^{43, 44}

Anticonvulsants

Older anticonvulsants, particularly carbamazepine, phenytoin, or valproate, were used extensively in the past to treat neuropathic pain. Potential adverse effects required screening, particularly for neutropenia, megaloblastic anemia, and others. Gabapentin has been shown to demonstrate analgesic properties in both animal and human models of neuropathic pain. Two well-designed, randomized, controlled multicenter studies evaluated the efficacy of gabapentin in postherpetic neuropathy and diabetic neuropathy.^{45, 46} Using doses of up to 3600 mg/day, mean daily pain intensity scores decreased significantly, and other secondary outcome measures, such as sleep and mood, improved when compared with the results in the placebo groups. Dizziness and somnolence, the most common adverse effects, appear to be reduced with slower upward dose titration. Pregabalin acts at the same receptors as gabapentin, but has better bioavailability and is easier to titrate.^{47, 48}

Local Anesthetics

Lidocaine (5%) patches have been found to reduce pain related to postherpetic neuropathy without any significant plasma levels of drug even with application of up to three patches per day.⁴⁹ Intravenous lidocaine infusions are gaining acceptance in a variety of pain management settings, from pain clinics to hospices.⁵⁰ Intravenous lidocaine 1–2 mg/kg is given over 15–30 minutes. If effective, a continuous infusion of 1–2 mg/kg/hr is started. The analgesic effects can be as prolonged as weeks of relief. Perioral numbness is an early warning sign of potential toxicity. Hepatic dysfunction and significant cardiac conduction abnormalities are relative contraindications to the treatment, viewed in balance with the patient’s goals of care and prognosis. Epidural or intrathecal administration of a local anesthetic, alone or in conjunction with an opioid, may provide pain relief in patients who are not candidates for systemic delivery.

N-Methyl-d-Aspartate Antagonists

Ketamine and dextromethorphan are NMDA receptor antagonists that are being explored for their use in neuropathic pain. Despite promising case reports regarding ketamine, adverse effects (including hallucinations) have limited its use. Methadone is believed not only to bind to opioid receptors but also to be an antagonist to the NMDA receptor as well. Therefore, this opioid is often considered when treating neuropathic pain. Magnesium, known to block the NMDA channel, has been given intravenously to patients with malignant neuropathic pain and has been reported to provide relief.⁵¹ Additional studies are needed.

Anticancer Therapies

Antineoplastic or radiation therapy may produce a reduction in tumor burden sufficient to alleviate pain, although the individual’s risks for complications or adverse effects, as well as the goals of care, must be carefully weighed. Unfortunately, little research has evaluated the analgesic effect of various chemotherapeutic regimens, instead focusing primarily on tumor regression. Radiation therapy is extremely effective in the management of several pain states, particularly pain associated with bone metastases.⁵² Bone metastases are occasionally seen in advanced uterine, cervical, or ovarian tumors. Approximately 75% of all patients treated for pain due to bone metastases obtain some level of relief, and almost half become pain-free. Surgery may be indicated to relieve pain in certain cases. For example, in cases of severe pelvic pain associated with cervical, vaginal, or vulvar cancers, pelvic exenteration can provide palliation of pain, bleeding, and complications associated with fistula formation.⁵³ Patient selection is critical, as is informed consent, particularly regarding potential motor dysfunction and care of resultant ostomies. Results suggest that in carefully selected patients, 50–85% are satisfied with their results.

Others

Although bone metastases associated with gynecologic malignancies are not as common as with other cancers, this does occur and can be quite painful. In addition to the therapies previously mentioned, bisphosphonates (pamidronate, zoledronate) can be useful in relieving bone pain.

A potentially promising area in the field of chemotherapy-induced peripheral neuropathy, highly prevalent in woman with ovarian cancer, is prevention of neuropathy. For example, studies are under way that evaluate the use of acetyl-L-carnitine or other neuroprotective agents to prevent chemotherapy-induced peripheral neuropathies.⁵⁴ Additional research is needed.

Intrathecal or epidural opioids in combination with local anesthetics produce effective analgesia with minimal side effects. Neuroablative techniques such as chemical or surgical rhizotomy likewise can be effective in resistant pain. Sympathetic blockade via phenol ablation of the superior hypogastric nerve plexus may relieve perineal pain. Case reports suggest the use of midline myelotomy in patients with intractable pain unrelieved by less invasive measures.⁵⁵

Bowel obstruction, dyspnea, anxiety, depression, and other symptoms are common in the face of advanced gynecologic malignancies or as a result of complications of treatment. Palliation of these symptoms, which are frequently linked with pain, can result in improved pain control and enhanced quality of life. Bowel obstruction is common in progressive ovarian cancer, and the majority of patients with bowel obstruction will die within 6 months. Palliation can include surgery in selected cases or, more commonly, intravenous or subcutaneous octreotide, nasogastric tube suction, and venting gastrostomy, in addition to analgesics and antiemetics.⁵⁶

Women with advanced gynecologic malignancies frequently experience dyspnea related to lymphangitic spread, pulmonary parenchymal replacement, or pleural effusions. Opioids are the first drug of choice, often in small doses that do not cause sedation. Short-acting anxiolytics are indicated in the face of severe anxiety. Simple measures such as bedside fans can provide additional comfort.

Depression is often poorly recognized in people with cancer.⁵⁷ Diagnosis is difficult in advanced disease because the usual physical symptoms of depression (fatigue, anorexia, and sleep disturbance) can result from the disease itself and its treatment. Psychological symptoms suggestive of depression in the cancer patient include loss of self-worth, unremitting sadness and hopelessness, and suicidal ideation. In fact, there is evidence that a simple screening question, “Are you depressed?” or “Are you sad?” is the most valid measure of a patient’s depression.⁵⁸ Supportive psychotherapy may be of benefit. Antidepressant medications, such as SSRIs including citalopram, fluoxetine, paroxetine, and sertraline are usually well tolerated. Unfortunately, the onset of effect can be 2 to 4 weeks, too long for patients with advanced disease and a very short life span. “Atypical antidepressants” (bupropion, mirtazepine, and venlafaxine) have a relatively rapid onset of action and few reported side effects. However, for patients with a very limited lifespan, stimulants such as methylphenidate and pemoline provide rapid relief, usually within hours to days.

Of the many symptoms affecting those with cancer, pain is the most feared. Thorough, ongoing assessment is critical in determining the pain syndromes involved and selecting the most appropriate analgesic therapies. When standard pharmacologic therapies are ineffective or produce intractable adverse effects, interventional techniques are warranted. Concomitant emotional and physical symptoms are common in women with pain due to gynecologic cancers. Physicians must be aware of treatment strategies to provide optimal palliative care — diminished pain, reduction of suffering, and enhanced quality of life.