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Palliative Care Consultations in Gynaeoncology$

Sara Booth, Eduardo Bruera, and Teresa Tate

Print publication date: 2004

Print ISBN-13: 9780198528067

Published to Oxford Scholarship Online: November 2011

DOI: 10.1093/acprof:oso/9780198528067.001.0001

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Pelvic pain syndromes and their management in advanced gynaecological malignancy

Pelvic pain syndromes and their management in advanced gynaecological malignancy

Chapter:
(p.45) Chapter 4 Pelvic pain syndromes and their management in advanced gynaecological malignancy
Source:
Palliative Care Consultations in Gynaeoncology
Author(s):

Sebastiano Mercadante

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780198528067.003.0004

Abstract and Keywords

Gynaecological malignancies constitute approximately 20 per cent of visceral cancers in women. Cancer in the pelvis causes progressive pelvic and perineal pain and complications such as uteretic obstruction with uremia, and lymphatic and venous obstruction. It also causes bowel or bladder outlet obstruction when the tumour invades the rectum or the bladder. Adding to these complications are significant anatomical and functional damages caused by invasive oncological treatments. One of the serious problems caused by neurotoxic chemotherapy, vulvectomy, vaginectomy, hysterectomy, pelvic exenteration, and other treatments is pain. This chapter covers the pathophysiology and pharmacological treatment of pelvic pain in gynaecological malignancies. The basic principles of care are not treated here; rather the focus is on the anatomy of the pelvis and the pathophysiological mechanisms of pain in order to understand pain and pain management. The chapter also includes some general methods of managing pain through the use of oral medications and interventional procedures.

Keywords:   gynaecological malignancies, visceral cancers, pelvis, progressive pelvic pain, perineal pain, pain, pathophysiology of pain, pharmacological treatment, pelvic pain, pelvic anatomy

Introduction

Gynaecological malignancies constitute approximately 20% of visceral cancers in women. Locally advanced cancers in the pelvis produce progressive pelvic and perineal pain, as well as other complications, including ureteric obstruction with uraemia, and lymphatic and venous obstruction. Invasion of the tumour into the rectum or bladder can lead to erosion with bleeding, sloughing of tumour into the urine or bowel, and bladder or bowel outlet obstruction.

Ovarian cancer is associated with recurrent episodes of bowel obstruction, paraneoplastic syndromes including peripheral neuropathies, and disturbances of the CNS, all of which can cause severe pain.

Oncological treatments may cause significant anatomical and functional damage, and even patients with advanced disease may receive one or more of the chemotherapeutic regimens currently in use. Serious local problems can develop as a result of neurotoxic chemotherapy, external beam radiation, radiation implants, hysterectomy, vulvectomy, vaginectomy, pelvic exenteration, and other treatments. Pain is the most frequently reported symptom complicating therapy.

This chapter focuses on the pathophysiology and pharmacological treatment of pelvic pain in gynaecological malignancy—the basic principles of palliative care are not discussed. The management of pain accompanying bowel obstruction is discussed in Chapter 7.

It should always be remembered that pain is a somato-psychic experience and the social, psychological, and spiritual aspects of pain need the same attention as the medical, if pain is to be managed effectively. Pain management cannot be achieved without an understanding of the pathophysiology of pelvic pain syndromes and this needs to be integrated with general palliative care management to achieve the best possible pain control. (p.46)

Table 4.1 Causes of pain in patients with gynaecological malignancies—in order of incidence

1. Direct nerve damage caused by tumour infiltration or inflammatory changes in the pelvis

2. Compression of adjacent structures by enlarging tumour masses

3. Neuropathies due to treatment of the cancer (post-surgical, post-radiotherapy, or neurotoxic chemotherapy)

4. Malignant invasion of sacral bone or distant metastases

5. Peri-tumoural oedema, infection, or necrosis surrounding adjacent structures

6. Obstruction of hollow viscus by tumour

7. Malignant invasion of the rich muscular structure of the pelvis

8. Vascular occlusion

9. Manifestations of paraneoplastic syndromes

There are many causes of pain in patients with gynaecological malignancy—for example:

  • lumbar pain due to iliopsoas muscle involvement;

  • nerve trunk pain, often radiating to lower limbs due to the involvement of lumbosacral plexus;

  • tumour involvement in the presacral area;

  • radiculopathy related to retroperitoneal spread.

A full list is set out in Table 4.1.

Anatomy

The pelvis is an inverted truncated cone continuous with the abdominal cavity. It contains viscera, muscles, ligaments and joints, vessels and nodes, nerves, and the skeleton of the pelvis. It is bordered by the pubic crest and the obturator muscle anterolaterally, sacrum, coccyx, and piriform muscle posterosuperiorly, and interiorly by the muscles of perineal floor. The viscera within the pelvis are supplied by sympathetic and parasympathetic nerves that contain both afferent and efferent fibres. The superior hypogastric plexus is situated in front of the bifurcation of the abdominal aorta. At its lower border, the plexus divides into the right and left hypogastric plexus. It gives off branches to the ureteral and testicular or ovarian plexuses, the body of uterus and the cervLx, and supplies the transverse colon, splenic flexure, and descending colon. The inferior hypogastric plexus supplies pelvic organs including the rectum, urinary bladder, prostate, uterus, and vagina. The pudendal nerve, branches of ilioinguinal, genitofemoral, and anococcygeal nerves innervate the perineum.1

(p.47) Mechanisms of Pain

Different pathophysiological mechanisms underlie different clinical pain syndromes. The pain syndromes associated with gynaecological malignancy are related to the characteristics and progression of the underlying disease including the preferential sites of metastases, which vary with each primary site. In order to develop rational, clinical treatment strategies for each pain that a patient suffers, it is important to have an understanding of the neuro-physiological changes that cause them.

Cancer pain Classification

Pain related to malignant disease can be classified as nociceptive (somatic and visceral) and neuropathic.

Somatic and visceral pains involve direct activation of nociceptors, and often complicate infiltration of tissue by tumour or tissue damage as a consequence of oncological treatments.

Neuropathic pain may be a complication of injury to the peripheral or central nervous system and is often poorly tolerated and difficult to control.

Temporal patterns of pain

The following terms describe different patterns of pain. Whatever the cause of the pain the clinician needs a good understanding of its timing in order to treat it effectively.

Breakthrough pain

This term refers to intermittent exacerbations of pain that can occur spontaneously or in relation to specific activity, especially at the end of the dosing interval of the regularly scheduled analgesic.

Incident pain

This is a sort of breakthrough pain. Some pains may be only moderately severe or absent whilst the patient is at rest but are exacerbated by different movements or positions, such as standing, walking, sitting, turning, deep breathing, coughing or with pressure on the area of involvement—this is called incident pain.

Incident pain is a very difficult to manage successfully as although the exacerbation associated with movement can be very short—lived it is often very severe and incapacitating for the patient. For example, a bed-bound patient with a fractured neck of femur may develop bedsores in their anxiety to keep absolutely still because of severe short-lived pain provoked by movement.

(p.48) Incident pain is not always preventable, even if predictable. It is the best known type of breakthrough pain and is commonly caused by bone metastases or is found in association with neuropathic pain (see below).

Nociceptive Pain

No specific histological structure acts as a nociceptive receptor. Α-delta and C-fibres have been clearly identified as having high-threshold transducers, which become involved as the intensity of the injuring stimulus increases. A repeated and intense stimulus induces the release of several inflammatory mediators, which may:

  • reduce the threshold for activation;

  • increase the response to a given stimulus; or

  • induce the appearance of spontaneous activity.

Various chemicals are released into damaged tissue cells. Substance Ρ is able to induce the production of nitrous oxide, a vasodilatator, and the degranulation of mast cells with a further vasodilatation and subsequent extravasation and release of bradykinin. The enhanced release of substance Ρ and other neurokinins may be the reason that the NMDA receptor for the excitatory amino acids becomes more easily activated. These transmitters together activate spinal cord neurones. The activation of NMDA receptors will result in an amplification of the response underlying central hyperalgesia. The repetition of a constant intensity C-fibre stimulus induces the phenomenon of “wind-up”, that is a switch from a low-level of pain-related activity to a high level without any change in the inputs arriving in the peripheral nerves. It has been suggested that nitric oxide (NO) feeds back to increase the release of C-fibre transmitters, further enhancing pain transmission.2

Somatic Pain

Somatic pain is caused by stimulation of nociceptors by direct extension of the tumour through fascial planes and their lymphatic supplies. Nociceptors are found in the integument and supporting structures, i.e. striated muscles, joints, bones (including periosteum), and nerve trunks. Pain is the result of somatosensory input generated by sensory signals from these tissues. Somatic pain is usually well localized and constant. Deep somatic pain is associated with cutaneous hyperalgesia, tenderness, reflex muscle spasm, and sympathetic hyperactivity.

Bone pain

Bone metastases are a major problem in advanced cancer and frequently give rise to complications that can have a devastating impact on the woman's quality of life. Complications include difficulty walking, even complete immobility, neurological deficits, and pathological fractures. (p.49)

Table 4.2 Cancer pain syndromes associated with direct tumour involvement of vertebral bodies in gynaecological malignancy

Vertebral body syndrome

Symptoms and signs

T12-L1 syndrome NB: imaging of pelvic bones alone will miss cause of pain, need soft tissue too.

Dull aching, mid-back pain exacerbated by lying or sitting, relieved by standing. Pain can radiate in girdle-like band anteriorly or to both paraspinal and lumbosacral area. May be referred to sacroiliac joint and superior iliac crest.

Sacral syndrome

Destruction of sacrum leads to severe, aching, focal pain in low back or coccygeal area, radiating to buttocks, perineum or posterior thighs. Insidious onset. Exacerbated by lying, sitting, relieved by walking. Increasing pain with perianal sensory loss. Bowel, bladder dysfunction may develop. Lateral extension may cause incident pain in hip. Local invasion of sacral plexus may occur.

C. F. and Booth, S. (1998). A pocket book of pain, 1st edn. Churchill Livingstone

Incident pain (see above), which is frequently associated with bone metastases, is usually difficult to control with drug therapy alone. It is important to warn patients that complete control of pain is difficult when there is a component of incident pain.3

Direct tumour involvement of the pelvic bony skeleton is also possible in advanced gyanecological malignancy: various syndromes have been described (Table 4.2).

Mechanisms of bone pain

The resorption of bone as a result of increased osteoclastic activation decreases bone density and disrupts skeletal architecture, either focally or throughout the skeleton. Periosteum is usually very pain-sensitive, as the density of myelinated and unmyelinated afferent fibres is high. Microfractures may occur in bony trabeculae at the site of metastases resulting in bone distortion.

Pain occurs because of one or more of the following:

  • the stretching of periosteum by tumour expansion;

  • mechanical stress of the weakened bone;

  • nerve entrapment by the tumour; or

  • direct destruction of the bone with consequent collapse

Bone pain typically develops insidiously over a period of weeks or months, becoming progressively more severe. The pain is characteristically described as dull, constant, and of gradually increasing intensity. Moreover, pain from bone metastases can produce a variety of symptoms.1

(p.50) Bone metastases and breakthrough pain

Internal fixation and radiotherapy are central to the management of bone metastases but the former may not be possible because the patient is too ill and there may be a delay in providing the latter. Patients with pain from bone metastases on weight-bearing or movement, may require a dose of opioid that causes excessive adverse effects for the patient at rest, as movement-related pain is likely to be repetitive and in some cases unpredictable.

A specialist pain/palliative care opinion is usually needed as spinal analgesia or a nerve block may be required.

Visceral Pain

Pelvic viscera have complex innervation from the peripheral nervous system. Visceral nociceptors have a wide range of responses, and may be activated in the presence of inflammation or tissue injury. Therefore, visceral afferents are considered polymodal, giving excitatory response to different stimuli, including inflammation, stretching, and distension.5

Neurones that transmit visceral sensory information to the spinal cord have cell bodies in the dorsal root ganglia. These primary afferents travel through the paravertebral ganglia, through the pre-vertebral ganglia from the sensory endings in the viscera themselves. Afferent fibres travel in conjunction with motor fibres of parasympathetic and sympathetic nervous system. Most visceral afferents have relatively slow conduction velocities.

Visceral pain tends to be diffuse because of the absence of a separate visceral sensory pathway and the low proportion of visceral afferent nerve fibres compared with those of somatic origin. Thus, the neurological mechanisms responsible for visceral pain differ from those involved in somatic pain. Most solid viscera are not sensitive to pain, and some stimuli, such as cutting, may be less painful than expected. Pain is diffuse, poorly localized and can be referred to other anatomic locations—‘referred pain’—and is often associated with motor and autonomic reflexes. One common example is shoulder pain due to diaphragmatic irritation from large subdiaphragmatic masses in ovarian cancer. Gross abdominal distension, from ascites, may also induce shoulder pain and hiccough.

Better localization of painful stimuli occur when the disease involves a somatically innervated structure such as the parietal peritoneum.

Other painful stimuli

Mechanical stimuli, such as torsion or traction of mesenteries, distension of hollow organs, stretch of serosal and mucosal surfaces, and compression of some organs is painful. These conditions are frequently observed in patients with advanced pelvic malignancies.

(p.51) Renal colic

Ureteric obstruction in the pelvis is common in advanced cervical cancer and the distension of the ureter and renal pelvis causes renal colic. Pain is also related to pressure in the urinary bladder.

Movement of the bladder or bowel may also induce colicky breakthrough pain in patients whose analgesic regimen is generally satisfactory.

Ischaemic pain

Ischaemic pain occurs particularly in tissues involved in metastatic disease or those recently damaged by surgery. Ischaemia may act as a modulator of mechanoreceptive visceral inputs. The variability of response to ischaemia may be due to any pre-existing pathology or to cancer related mechanical distortion of the pelvic organ secondary to local changes.

These models of visceral pain help to explain a disappointing result from some neurolytic blocks given for pelvic cancer pain or a poor response to analgesic drugs. Failure or partial success of a hypogastric plexus block may be attributed to the fact the tumour has metastasized beyond the nerves that conduct pain via the plexus and the component nerves that form it.

Neuropathic Pain

Neuropathic pain is defined as pain resulting from damage to the peripheral or central nervous systems. It most commonly occurs as a consequence of tumour compression or infiltration of nerves contained in the pelvis, or nervous structures close to the sacrum.

Many patients with advanced gynaecological malignancy develop neuropathic pain: due to nerve damage or sensory loss that is described as numbness, burning, crawling sensation, and tightness.

Neuropathic pain is associated with some characteristic symptoms such as:

  • allodynia—pain which follows a normally innocuous stimulus such as light touch;

  • hyperalgesia—pain of abnormal severity following a noxious stimulus;

  • hyperpathia—increased pain in an area of increased sensory threshold.

Neuropathic pain has a variable onset, as it can be continuous, spontaneous, or paroxysmal.

It has been suggested that hyperalgesia reflects a sensitization of receptors, while allodynia is a central phenomenon mediated by large myelinated fibres. Pain may be either superficial or deep. Referred and abnormal pain radiation, such as the presence of abnormal sensations and pain over large areas of skin, are typically observed in myelopathies. The degree of radiation and referral is likely a reflection of a progressive recruiting of wide range neurones in deeper layers of the dorsal horn. Moreover, an increased activity is seen in sympathetic (p.52) efferents following sensitization of C-nociceptors with spontaneous discharges in C-fibres and maintained in part by alpha-1 receptors. Some common neuropathic pain syndromes are illustrated in Table 4.3.

Aetiology of Neuropathic Pain In Gynaecological Malignancy

Direct nerve infiltration

The abundant nerve supply to the pelvis is vulnerable to direct malignant infiltration which can result in, for example, lumbosacral plexopathies from the invasion of perineal nerves. This causes poorly localized dull aching pain in the thighs (for example) and may be accompanied by symptomatic sensory loss, causalgia, and deafferentation syndromes (see Table 4.3).

Direct pressure on nerves by metastatic disease

Metastatic disease may cause lumbrosacral plexopathies, spinal cord or cauda equina syndromes.

Table 4.3 Cancer pain syndromes in advanced gynaecological malignancy caused by direct nerve infiltration

Nerve(s) infiltrated by tumour

Symptoms and signs

Lumbrosacral plexopathy Associated with local extension of advanced gynaecological malignancy including sarcomas plus other primary sites e.g. NHL Lumbar plexus: L1–4: (anterior primary rami) lies on paravertebral psoas muscle.

Pain earliest symptom, dull, aching, constant. Upper plexopathy (30% pts) c/o pain in back, lower abdomen, flank, iliac crest, anterolateral thigh. Sensory symptoms/signs in L1–4 distribution. May also have pain on flexion of ipsilateral hip (‘malignant psoas syndrome.’)

Sacral plexus = L4–5 trunk & S1–3 (anterior primary rami)

Lower plexopathy most common 〉50% patients. Usually pelvic tumours. Pain in buttocks, perineum, posterolateral part of the leg. May have sensory changes and weakness in L5-S1 distribution. Bladder and bowel dysfunction and leg oedema may be present.

Sacral plexopathy Occurs frequently in patients with advanced gynaecological malignancy also common in colonic and genitourinary malignancy. NB CT/MRI scanning necessary to assess lumbrosacral plexopathy

Dull, aching midline pain. Local extension of a sacral/presacral mass. Sensory loss beginning in presacral area. Sensory findings commonly unilateral at first then progressing to bilateral sacral sensory loss and autonomic dysfunction. Numbness over dorsal medial foot and sole, weakness of ankle dorsiflexion and inversion. Bladder and bowel dysfunction possible. Patient may be unable to lie or sit down because of pain.

C F. and Booth, S. A pocketbook of pain, 1st edn, (1998) pp 231. Churchill Livingstone

(p.53) Viral infections

All patients with advanced cancer are immunocompromised by the effects of the underlying disease. This may be compounded by drug therapy such as corticosteroids.

Rectal neuralgia from herpes zoster is the cause of a well-recognized syndrome, proctalgia fugax.

Adverse effects of drugs used in chemotherapy

Mono- and polyneuropathies, may be induced by vincristine, paclitaxel, and cisplatin therapy. Pain is characterized by paresthesia distally and neurological changes such as arreflexia and sensory changes may be found on examination. Patients may walk with a wide-based gait because of loss of proprioception—the pain can be very severe and resistant to standard therapies for neuropathic pain. The pain frequently resolves, at least partially, over months, sometimes years.

Radiation-induced nerve damage

Radiation can produce many of the same clinical pain syndromes as the disease itself but these occur months or years after the original treatment and they have become much more unusual as it has become possible to give lower total doses using longer courses of smaller fractions with much more precision.

Neuropathic cancer pain is varied in presentation, irreversible, and difficult to treat. Once established, neuropathic pain (with accompanying spinal hyper-excitability) is independent of the afferent input: this is why it is so difficult to control.

The multiple mechanisms underlying the pathophysiology of neuropathic pain may explain the differential sensitivity to opioids, as different nerve injuries and the dynamic course of the illness initiate varying degrees of neuronal plasticity and influence the responsiveness to opioids.6

Treatment

The current treatment of nociceptive pain is based on the WHO analgesic ladder, which sets out a graduated approach to the use of analgesic drugs: it is a framework of principles rather than a rigid protocol (see Fig. 4.1).

Step 1:

Pharmacological studies have demonstrated that a broad spectrum of analgesics is effective in cancer pain. NSAIDs are the drugs commonly used as first step of the analgesic ladder and their usefulness for both somatic and visceral pain has been demonstrated. They are also effective in combination with opioids, regardless of the pain mechanism involved. NSAIDs have been shown to have useful opioid-sparing effects in long-term studies and to maintain this for prolonged periods of time.7

Steps 2 and 3 of the analgesic ladder:

When cancer patients experience severe pain, opioids are the mainstay of therapy.8 There are many ways of delivering (p.54)

                   Pelvic pain syndromes and their management in advanced gynaecological malignancy

Fig.4.1 WHO three-step analgesic ladder.

opioids in the management of cancer pain. In some clinical situations, there are clear indications for using one preparation or delivery system over another; for example:
  • the potential or actual complications associated with that system;

  • the efficacy of that system to deliver acceptable analgesia;

  • the ability of the patient to use a specific type of delivery system;

  • the complications associated with that system;

  • ι he ease of use for the patient and her family; and

  • cost is another important consideration both for those patients who purchase their own medication and for health care providers which, across the world, are under pressure to contain costs.

Oral Route

The oral route is the one most commonly used. It has several advantages—it is the safest, the least invasive, the least expensive, and the easiest route for opioid administration for most patients with cancer pain. In all patients who can take oral medication, this route should be considered first. The main problem with the oral route is the first-pass biotransformation of opioids in the liver. All opioids (p.55) given orally are absorbed via the gastric and duodenal mucosa and then transported to the liver via the portal venous system. In the liver, the drugs undergo ‘first-pass metabolism’ before entering the systemic circulation. As there is huge inter-individual variation in the degree of first-pass metabolism, conversion between oral and parenteral routes can only be approximate. After making a change the patient requires careful monitoring for signs of inadequate analgesia or a relative overdose of opioid.

First-pass metabolism has a major impact on the systemic plasma concentrations of drugs. For example, the dose of morphine given orally to a patient with cancer pain must be two to three times the intravenous or subcutaneous dose. This is true of other opioids.

Oxycodone is roughly equipotent to morphine if given parenterally, but appears to be approximately twice as potent as morphine when given orally because of less first-pass metabolism.

Modified-release Preparations

Morphine is the most commonly used medication in the world to treat moderate to severe cancer pain. As it has a short duration of effect when used in an ‘immediate release’ form, several preparations have become available to provide longer lasting analgesia. Bioavailability of these modified-release preparations is the same as that of immediate-release preparations, but time to peak plasma drug concentrations is longer, and peak plasma concentration is decreased. Recommendations for most of these preparations state that they should be administered every 12 h. Clinicians occasionally use an 8-h schedule, if necessary, to provide adequate analgesia, but this is not standard practice. There are other preparations, such as a morphine pellet coated with a polymer, which can be administered once every 24 h.

Specific Issues With Breakthrough Pain

If additional opioid analgesia is needed for ‘breakthrough’ pain, doses of a fast-onset, short-acting opioid preparation should be available to the patient. However, most immediate-release oral opioid preparations take approximately 30 min to the onset of analgesic action when taken on an empty stomach, and faster routes may be required, such as the subcutaneous or transmucosal routes (see below).

The Rescue Dose

A rescue dose of opioid can provide a means of treating breakthrough pain in patients already stabilized on a baseline opioid regimen. The use of an opioid, with short half-life, such as immediate-release morphine or hydromorphone, is suggested. The size of the most effective dose remain unknown, although clinicians suggest a dose roughly equivalent to 5–10% of the total opioid dose (p.56) administered as needed every 2–3 h. (Editor's note: one-sixth of total 24-h dose is standard in UK at present.) However, the onset of action of an oral dose may be too slow (more than 30 min) and better results may be obtained with a parenteral rescue dose. Although the intravenous route is the fastest, subcutaneous administration is associated with an acceptable onset of effect and should be considered equivalent in terms of efficacy. PCA may be an option for both routes.

Fentanyl Lozenges

Oral transmucosal dosing is a recent non-invasive approach to the rapid onset of analgesia. Highly lipophylic agents may pass rapidly through the oral mucosa avoiding the first-pass metabolism achieving active plasma concentrations within minutes. Fentanyl, incorporated in a hard matrix on a handle, is rapidly absorbed. It has been shown to have an onset of pain relief similar to intravenous morphine that is within 10–15 min. When the fentanyl matrix dissolves, approximately 25% of the total fentanyl concentration crosses the buccal mucosa and enters the bloodstream. The remaining amount is swallowed and about one-third of this part is absorbed, thus achieving a total bioavailability of 50%. Different controlled studies have shown the effectiveness of oral transmucosal fentanyl for treating episodes of breakthrough pain.

It is important to stress that the effective transmucosal dose is not correlated with the basal analgesic regimen of transdermal fentanyl, underlining the need to individuali/.e the dose.9

Switching Opioid

Different opioids have different effects on the subsets of opioid receptors in the central nervous system and ‘cross tolerance’ between opioids is incomplete. This can be exploited when the adverse effects of one particular opioid are making it unacceptable to an individual as an analgesic and cannot be controlled. In these circumstances a change from one opioid to another is sometimes a useful option. Oxycodone, methadone, and hydromorphone are possible alternatives to oral morphine.

Methadone

Methadone in particular, has interesting extra-opioid properties, such as inhibition of NMDA receptors, which are useful in giving additional analgesia and a low rate of tolerance.

The degree of cross-tolerance may change as the dose of opioid is increased and care must be taken in applying an equi-analgesic dose formula to patients on high doses of any opioid, but this is particularly important when switching (p.57) them to methadone.10 Moreover, methadone's potency may be much greater than expected when a switch is made from another opioid because tolerance is reversed, probably due to its anti-NMDA effect. Methadone should only be used by specialists or on specialist advice.

Strict surveillance is necessary when converting patients taking high doses of one opioid to another drug in the same class.

Adverse Effects

Patients will develop tolerance to most of the undesirable side-effects of opioids (such as nausea/vomiting or sedation) over a period of several days. Tolerance rarely develops to constipation but there is great inter-individual variation in the severity of this symptom and the amount of treatment it requires.

If patients continue to have unacceptable adverse effects in spite of active management and appropriate use of opioids, it may be necessary to use another opioid of equivalent efficacy.

Parenteral Route

The oral route is not suitable for every patient. Possible reasons include:

  • oesophageal motility problems (e.g. head and neck cancer, oesophageal cancer);

  • gastro-intestinal obstruction (bowel obstruction from ovarian cancer);

  • uncontrollable nausea and vomiting (e.g. bowel obstruction);

  • swallowing difficulties because of the site of their cancer (e.g. head and neck cancer);

  • co-existing non-malignant conditions such as neurological impairment;

  • being unconscious, comatose or very drowsy—most dying patients who have been on regular analgesics will require them parenterally to give good symptom control when they can no longer take drugs by mouth.

In these situations alternative routes such as subcutaneous, intravenous and transdermal should be considered.8

Subcutaneous Route

This simple method of parenteral administration is now commonly used in palliative care and has largely replaced other alternative routes to oral administration where syringe drivers are available. It involves inserting a small plastic cannula under the skin of the chest, abdomen, upper arms, or thighs and attaching the tubing to an infusion pump.

(p.58) Drugs may be administered as a bolus or continuous infusion. A subcutaneous opioid takes about 20 min to start having an effect reaching a peak within 40 min: the duration of action depends on the half-life of the drug.

The limiting factor for continuous subcutaneous infusion is the volume of fluid that can be injected per hour and concentrated solutions of drugs are helpful.

Most drugs used by intravenous route can also be used by the subcutaneous route, although pain and irritation are possible with methadone. Advantages of the subcutaneous route include:

  • no need for intravascular access;

  • changing sites of infusion can be easily accomplished;

  • dangerous infection and the other complications of the intravenous route can be avoided.

Disadvantages include:
  • need for subcutaneous pump, which is relatively costly and needs correct maintenance;

  • may need two pumps to deliver drugs which would be incompatible in the same syringe.

The subcutaneous syringe driver has been a great advance in palliative care in the last 30 years—before its widespread use many dying patients had to be given four hourly injections to maintain their comfort in their last days or hours.

Intravenous Route

This is indicated for those patients:

  • whose pain cannot be controlled by a less invasive route;

  • who already have central venous access;

  • who need parenteral medication but have very low platelet counts.

It is mostly used in haematology patients and will not often be used for patients with advanced gynaecological malignancy.

Advantages include:

  • rapid onset of action allowing for an almost immediate effect in emergency conditions;

  • no first-pass metabolism therefore more predictable dosing requirements;

  • consistent delivery—poor peripheral perfusion can reduce the amount of drug absorbed when subcutaneous/intramuscular routes are used.

Disadvantages include:
  • it is complex to manage and requires a higher level of training in professional staff, which makes it less easy, but not impossible, to use in home care;

  • (p.59) bolus doses of opioids (or benzodiazepines) can cause respiratory depression;

  • the equipment is needed to deliver intravenous (IV) drugs is more expensive and elaborate;

  • the speed of administration must be particularly carefully controlled;

  • infection of central or peripheral venous lines can be very uncomfortable and may cause life-threatening infections—this is a particular risk for the immunosuppressed.

A number of opioids are available in intravenous solution in most countries, including morphine, hydromorphone, fentanyl, alfentanil, sufentanil, and methadone.

Fentanyl and Sufentanil

Fentanyl is approximately 80–100 times more potent than morphine, and sufentanil is approximately 1000 times more potent.

Advantages include:

  • lower incidence of constipation, nausea, vomiting and sedation than morphine;

  • low incidence of histamine release;

  • low incidence of other adverse drug reactions;

  • no active metabolites;

  • useful in renal impairment because of absence of active metabolites and mostly excreted from GI tract

Disadvantages include:
  • high cost compared to morphine;

  • smaller range of different preparations available;

  • fentanyl is not suitable for routine IV administration, as it is a potent respiratory depressant

Patient-controlled Analgesia (Pca)

Intravenous or subcutaneous opioid infusions can be given as continuous infusions or by a patient-controlled analgesia (PCA) device, which provides a continuous infusion plus on-demand boluses. The PCA device should be set initially to deliver a continuous infusion with the bolus dose at 25% of the hourly dose and with a lock-out interval of 2 h. The bolus dose should be adjusted to provide supplementary analgesia, to counter or minimize breakthrough pain. ‘Lock-out’ intervals should be modified on the basis of clinical need.

(p.60) Contra-indications to using a PCA:

  • cognitive impairment;

  • patients dislike of the technical aspects of PCA;

  • patients who exhibit drug-seeking behaviour.

PCA has other drawbacks—it is invasive and it is associated with all the other complications inherent in the long-term use of subcutaneous needles or intravenous lines. The pump itself may limit patient mobility and the team caring for the patient requires a higher level of technical expertise.

The oral—parenteral ratio for morphine is 2:1 or 3:1.8

Transdermal Route

This is another non-invasive way of maintaining a continuous plasma concentration of opioid.

Fentanyl

A fentanyl patch consist of a reservoir of fentanyl (sufficient for about three days) in combination with alcohol. The patch releases fentanyl at a constant rate until the reservoir is depleted. Upon initial application of the patch, a subcutaneous ‘depot’ is formed as fentanyl saturates the subcutaneous fat beneath the patch. After 12–16 h, steady-state plasma fentanyl concentrations are reached, which are maintained for about 72 h. Fentanyl patches are currently available in 25, 50, 75, and 100 μg/h dosages. The bioavailability of transdermal fentanyl is very high, approximately 90%.

Advantages include:

  • it offers a non-invasive way of administering fentanyl to patients with stable pain in whom the 24-h opioid requirement has already been determined;

  • fentanyl is less constipating than morphine and this may offer a significant advantage to women with bowel dysfunction associated with abdomino-pelvic malignancy.

Disadvantages include:
  • Unsuitable for patients with uncontrolled pain.

  • Because of the slow depot formation and slow rise in plasma concentrations, this system is not suitable for patients with uncontrolled pain, as analgesia cannot be titrated rapidly.

  • Problems arise from conversion to fentanyl, as no clear protocols have been established. It has been suggested to use a conversion fentanyl-morphine ratio of 1:70–100. However, patients may still be under- or over-dosed and monitoring is essential until the correct dose has been established.

  • (p.61) Changes in rate of absorption with changes in body temperature—a feverish patient will absorb more fentanyl than one who is apyrexial because of vasodilatation in the skin.

  • Slow offset of action once patch removed—fentanyl levels fall gradually once a patch is removed: this must be remembered if another drug is being started such as a subcutaneous opioid. It is important to give a reduced dose of the new drug for the first 12 h or so (with rescue medication available) and monitor the patient carefully.

The Transmucosal/sublingual Route

This is another route that may be useful in those patients unable to tolerate either oral drug therapy (e.g. nausea, vomiting, or dysphagia) or alternative parenteral routes such as lack of venous access. Advantages include:

  • sublingual venous drainage is systemic rather than portal and therefore hepatic first-pass elimination can be avoided;

  • the transmucosal/sublingual route offers the potential for more rapid absorption and onset of action relative to the oral route.

Transmucosal Route and Breakthrough Pain

This route (see above) is particularly useful for treating breakthrough pain, particularly when the pain is sudden in onset and short-lived, in which case an oral dose of opioid would take too long to have any beneficial effect.

Transmucosal fentanyl is the only medication that has been found to be a very useful tool in the management of breakthrough pain in cancer patients in different controlled studies—it also has a lower incidence of adverse effects than oral morphine. It is discussed in detail above in section on breakthrough pain.

Rectal Route

This route may be a simple alternative when the oral route is not possible because of vomiting, obstruction, or altered consciousness. Advantages include:

  • independent of gastro-intestinal tract motility and rate of gastric emptying;

  • simple;

  • suitable for use at home by untrained carers or patients;

  • staff do not need a high level of technical expertise to use it.

(p.62) Disadvantages include:
  • wide inter-individual variation in amount of drug drained from the rectum;

  • absorption changed by surface area of rectum available for defecation;

  • absorption disrupted by defecation or constipation;

  • uncomfortable for prolonged use;

  • cannot be used if patient has painful anal conditions such as fissures or inflamed haemorrhoids;

  • does not bypass first-pass metabolism.

Dose equivalence

Opioids are usually given at the oral dose.

Adjuvants

An important approach to a patient with pain that is poorly responsive to opioids is the co-administration of a non-opioid analgesic. There are a very large number of options.

Anti-depressants

Anti-depressants may improve depression, enhance sleep, and decrease the perception of pain. However, the analgesic effect of tricyclics is not directly related to anti-depressant activity. Common side-effects of tricyclic compounds include antimuscarinic effects, such as dry mouth, impaired visual accommodation, urinary retention, and constipation, antihistaminic effects (sedation), and anti-alpha-adrenergic effects (orthostatic hypotension). The analgesic response, unlike an anti-depressant effect, is usually observed within 5 days. Alternative drugs with a lower incidence of side-effects should be considered in patients sensitive to the sedative, anticholinergic or hypotensive effects of amitriptyline. Despite the frequent use of amitriptyline in neuropathic cancer pain, its effectiveness has not been demonstrated appropriately in this context although good data is available for diabetic neuropathy for example.

Membrane Stabilizers for Neuropathic Pain

It has been suggested that an anomaly in ion channels may play a role in the molecular mechanism of neuropathic pain. Systemic local anesthetics (e.g. mexiletine), carbamazepine, phenytoin, and sodium channel blockers, have been reported to relieve neuropathic pain states. Although the exact mechanism of these drugs is not known, they all inhibit the sodium channels of hyperactive and depolarized nerves, while not interfering with normal sensory function. (p.63) Although cancer patients with neuropathic pain have been reported to benefit from lignocaine, controlled studies failed to demonstrate any significant benefit. Although sodium channel-blocking agents are useful for the management of chronic neuropathic pain, no conclusive clinical study has statistically verified these observations in cancer pain.

Anticonvulsant Drugs

Anticonvulsants, such as carbamazepine, phenytoin, valproate, and clonazepam, have been reported to relieve pain in numerous peripheral and central neuropathic pain conditions, although contradictory results have been found. Gabapentin is a promising drug as adjuvant to opioid analgesia for neuropathic cancer pain, although its superiority over amitriptyline has to be demonstrated.

Steroids In Neuropathic Pain

A number of studies have documented the positive effects of corticosteroids on various cancer-related symptoms, including pain, appetite, energy level, food consumption, general well-being, depression. However, most of the evidence for analgesic effects is anecdotal.

Clinicians sometimes use it when a tumour is thought to be pressing on a nerve with the intention of reducing peri-tumoural oedema and thereby reducing pressure on the nerve and possibly pain.

Bisphosphonates

Bisphosphonates have been found to potentiate the effects of analgesics in metastatic bone pain. Pamidronate, a potent bisphosphate, significantly reduced morbidity caused by bone metastases, including a 30–50% reduction in pain, impending pathological fractures, and the need for radiotherapy. Best results are obtained with doses of 60 or 90 mg pamidronate. This treatment is generally well-tolerated. Most investigators, primarily because of gastro-intestinal adverse events and the urgency of the situation, have preferred intravenous administration of bisphosphonates. Recently, zomepiramate (zoledronic acid), a stronger bisphosphonate, has been used.

Ketamine

Ketamine is a non-competitive NMUA receptor blocker that exerts its primary effect when the NMDA-receptor-controlled ion channel has been opened by a nociceptive barrage—it should only be initiated on the advice/under supervision of a specialist. A synergistic effect between ketamine and opioids has been (p.64) observed in cancer pain patients who had lost an analgesic response to high doses of morphine. Ketamine should be given at an initial starting dose of 100–150 mg daily, while the dose of opioids should be reduced by 50%, with the dose being titrated against the effect. The occurrence of adverse effects (such as hallucinations) may limit its analgesic efficacy.

Interventional Procedures

Spinal Route

A small number of patients may still not obtain adequate analgesia despite large systemic opioid doses and the use of adjuvant drugs, or they may suffer from uncontrollable side-effects such as nausea, vomiting, or sedation.

The goal of spinal opioid therapy is to place a small dose of an opioid and/or local anaesthetic close to the spinal opioid receptors located in the dorsal horn of the spinal cord to enhance analgesia and reduce systemic side-effects by decreasing the total daily opioid dose. Intrathecal opioid doses are one hundredth of the oral.

Epidural Or Intrathecal Placement?

Use of this route to deliver opioids requires placing a catheter into the epidural or intrathecal (subarachnoid) space and using an external or implantable infusion pump to deliver the medication. Deciding between epidural vs. intrathecal placement or external vs. implantable pumps to deliver the opioid is based on multiple factors, including duration of therapy, type and location of the pain, disease extent and central nervous system involvement, opioid requirement, and individual experience. The daily epidural opioid requirement is approximately ten times that of intrathecal administration. Intrathecal opioid administration has the advantage of allowing a higher concentration of drug to be localized at the receptor site while minimizing systemic absorption, thus possibly decreasing drug-related side-effects. These are specialist techniques.

Choice of Drug

Morphine and Local Anaesthetic Combinations

Morphine remains the drug of choice for the spinal route, because of its relatively low lipid solubility resulting in a slow onset of action, but a long duration of analgesia when given via intermittent bolus. The starting dose is quite difficult to calculate and should take into consideration the previous opioid dose, the woman's age, and the mechanism underlying the pain. Adding a local anaesthetic (bupivacaine or ropivacaine) to morphine via the spinal route has (p.65) been successful in providing good analgesia in patients whose pain was resistant to epidural morphine alone, despite high doses e.g. patients with neuropathic pain.

Morphine and Clonidine In Combination

Clonidine, an alpha-adrenergic agonist that acts at the dorsal horn of the spinal cord to produce analgesia, has been used in cancer patients in combination with epidural (or intrathecal) morphine infusions. There is some evidence to suggest that neuropathic pain may be somewhat more responsive to the combination of clonidine/morphine than to morphine alone, although orthostatic hypotension is of concern. This technique is still being evaluated.

Disadvantages include:

  • high level of specialist knowledge and experience is needed to know when these techniques are most appropriate and for placement of the delivery system;

  • introduction of infection: local infection may only require removal of catheter or delivery system but meningitis, epidural abscess and other CNS infections have been reported;

  • the delivery system may not function properly;

  • adverse drug reactions such as pruritus (opioids) or orthostatic hypertension (clonidine) are possible.11

Indications In Pelvic Malignancy

Spinal therapy can provide regional blockade for pelvic pain (nociceptive or neuropathic), incident neuropathic pain, or bony pain from metastatic disease in the vertebral column, pelvis, and lower limbs. These are all potentially difficult pains to manage on oral pharmacological therapy alone.

Hypogastric Plexus Block

It has been claimed that a superior hypogastric plexus block can be a highly effective method of controlling pelvic pain syndromes. It may not be completely effective however as pelvic tumours have a tendency to infiltrate somatic structures as well as nerves.

Pelvic cancers are often associated with myofascial involvement that causes somatic pain; pressure on the sciatic nerve frequently causes severe neuropathic pain. Therefore, the clinical picture is often mixed.

(p.66) In conclusion, patients must be carefully selected for interventions such as a hypogastric plexus block or a sympathetic block for visceral pelvic pain. Retroperitoneal invasion may result in a limited spread of neurolytic solution and this may be another reason for failure or only partial success of a nerve block.

Cordotomy

A percutaneous cordotomy is the interruption of the ascending spinothalamic tract, usually at the cervical level. A percutaneous cervical cordotomy by radiofrequency has been used in patients with unilateral bone pain below the C5 dermatome.

The procedure is associated with potentially serious complications including:

  • mirror pain, where a similar pain redevelops, sometimes with increased severity within weeks to months or the procedure;

  • general fatigue;

  • hemiparesis;

  • respiratory failure—the phrenic nerve has its origins variably in C 3,4, 5.

All these can cause a significant deterioration in the patient's performance status and quality of life, and are potentially hazardous.4

Summary

Pelvic pain syndromes in advanced pelvic malignancy commonly have a mixed aetiology requiring more than opioid therapy alone. The WHO pain ladder should be followed first and the oral route of opioid delivery should be the first choice. If the oral route cannot be used because of gastro-intestinal obstruction and/or severe nausea/vomiting, alternatives should be used, including transdermal, intravenous, or subcutaneous ones. As well as establishing an analgesic regimen, which provides continuous pain relief, analgesia should be provided for breakthrough pain, which needs to work within an appropriate period. If a rapid onset is needed, the subcutaneous, sublingual, or transmucosal routes (fentanyl lozenges) should be considered.

The spinal route could be used if the oral and other parenteral routes remain unsuccessful, despite trials with different opioids and the use of adjuvant drugs. Spinal analgesia may be most effective when opioids and local anaesthetics and/or clonidine are used in combination. Whatever route is used, administration of opioids to manage cancer pain requires knowledge of each drug's potency relative to morphine and bioavailability of the route (p.67) chosen. Patients should be closely followed and doses titrated to minimize side-effects, whenever the opioid, route or dose is changed. Interventional procedures, such as neurolytic blocks, are seldom necessary and are associated with several problems. Their role has not still substantiated in controlled studies.

References

Bibliography references:

1 Rigor, B. M. (2000). Pelvic cancer pain. J Surg Oncol, 75, 280–300.

2 Mercadante, S. and Portenoy, R. K. (2001). Opioid poorly responsive cancer pain. Part 2. Basic mechanisms that could shift dose-response for analgesia. J Pain Symptom Managet, 21, 255–264.

3 Mercadante, S. (1999). Treatment and outcome of cancer pain in advanced cancer patients followed at home. Cancer, 85, 1849–1858.

4 Mercadante, S. (1997). Malignant bone pain: pathophysiology and treatment. Pain, 69, 1–18.

5 Cervero, F. and Laird, J. M. A. (1999). Visceral pain. Lancet, 353, 2145–2148.

6 Besson, J. M. (1999). The neurobiology of pain. Lancet, 353, 1610–1615.

7 Mercadante, S., Casuccio, A., Agnello, A., Pumo, S., Kargar, J., and Garofalo, S. (1997). The analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain due to somatic or visceral mechanism. J Pain Symptom Manage, 17, 351–356.

8 Hanks, G. W. and the Expert Working group of the Research Network of the European Association for palliative care (2001). Morphine and alternative opioids in cancer pain: the EAPG recommendations. Br J Cancer, 84, 587–593.

9 Portenoy, R. K., Payne, R., Coluzzi, P. et al. (1999). Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain, 79, 303–312.

10 Bruera, E., Pereira, J., Watanabe, M., Belzile, M., Kuehn, N., and Hanson, J. (1996). A retrospective comparison of dose ratios between methadone, hydromorphone and morphine. Cancer, 78, 852–857.

11 Mercadante, S. (1999). Problems of long-term spinal opioid treatment in advanced cancer patients. Pain, 79, 1–13. (p.68)