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An overview of treatment strategies for cancer pain with a focus on interventional strategies and techniques
Practice Points
Amitabh Gulati*1, Jatin Joshi2 & Aisha Baqai2 Patients suffering from cancer-related pain syndromes have many pharmacologic options in
alleviating their specific symptoms. Interventional techniques in cancer-pain management are increasingly becoming part of the
continuum of treating a cancer patient’s pain. The sympathetic system is an important target for treatment of a cancer patient’s pain
syndrome. With newer imaging techniques, such as ultrasonography, peripheral nerves can be accurately
targeted for treatment of peripheral cancer-pain syndromes. Intrathecal drug delivery remains a vital technique in assisting patients with focal areas of pain
and the devices allow for delivery of medications that cannot be safely given systemically for pain control.
SUMMARY As the incidence of cancer increases, considerations for pain treatments become more important and varied. While traditional views on pain therapy are successful in treating the majority of cancer-related pain, a continuum has developed to include interventional strategies in addition to pharmacologic management. Further improvements in understanding anatomy in the context of imaging and pathophysiology of cancer-pain syndromes direct our current interventional pain management options. We discuss the current interventional treatment options regularly used in the cancer-pain population. Cancer affects more than a million people a year in the USA, and is the second leading cause of mortality [1]. In the advanced stages of cancer, pain is prevalent in 70–90% of patients, although less than half of patients get adequate pain relief [2]. Accordingly, pain is one of the major fears of cancer patients and significantly affects quality of life, coping mechanisms and the burden of the disease [3].
While up to 90% of cancer-related pain can be managed with basic pain management techniques focused on opioid medications, the remaining patients may benefit from alternative treatments [4]. Management of uncontrolled pain may be treated with chemotherapy, radiation therapy and surgical options. However, interventional pain therapies are available to improve both pain control and quality of life
Department of Anesthesiology & Critical Care, Board Certified in Anesthesiology & Pain Management, Memorial Sloan Kettering Cancer Center, M308, New York, NY, 10065, USA 2 Department of Anesthesiology, Weill Medical College, Cornell University, New York, NY, USA *Author for correspondence: Tel.: +1 212 639 6851; Fax: +1 212 717 3206; [email protected] 1
10.2217/PMT.12.61 © 2012 Future Medicine Ltd
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai in cancer patients with uncontrolled pain [5]. While pharmacologic therapy, primarily opioid and adjuvant medications, remains the mainstay for pain therapy, interventional approaches can serve as valuable modalities and adjuncts for pain management. Many nonpharmacologic techniques have been investigated for the management of cancer pain and resulting comorbidities including insomnia, depression and anxiety. However, in this article we aim to introduce the reader to various interventional techniques that are commonly offered to patients suffering with cancer-related pain. This is not an exhaustive list and some topics are only introduced and not comprehensively discussed. While risks and side effects of these procedures are not discussed in detail, some references are provided for the reader to refer to in the literature. We will also briefly discuss pharmacologic management options for these patients and add references for the reader regarding noninterventional treatment algorithms. Pharmacological management Cancer can cause pain that is somatic, visceral, referred or neuropathic in origin. For instance, back pain is a referred pain that is frequently seen with pancreatic cancer. Lesions of the nervous system may lead to neuropathic pain complaints, such as plexopathies from metastatic disease compressing the nerve bundle [6]. These different pain generators can be targeted by specific pharmacologic treatments. It is common for cancer patients to receive multimodal pharmacologic treatment for better pain control. Most cancer patients may be adequately treated with pharmacological methods and these are discussed briefly below. Introduced in 1986, the WHO ladder is a validated method of addressing pharmacologic management of cancer pain. Although no fourth step has been added formally to the classification system, interventional therapies can be used at any step in pain management [7]. Studies have supported the paradigm’s efficacy in relieving cancer-related pain; however, data suggests that adherence to the analgesic ladder and other pain guidelines are not consistent [8]. The first step of the WHO analgesic ladder includes nonopioid analgesics and adjuvant medications; however, these may be more effective in combination [9]. Because the etiology of cancer pain is complex, properties of various medications can target many different
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pain mechanisms (Table 1). Nonsteroidal antiinflammatory drugs, COX-2 inhibitors, acetylsalicylic acid, intravenous acetaminophen and corticosteroids target inflammation caused by cancers [10]. Adjuvant medications, such as antidepressants (e.g., nortriptyline) and anticonvulsants (e.g., gabapentin and pregabalin), are used to target neuropathic pain related to cancer [10,11]. Although only formally indicated to manage pain from fibromyalgia and peripheral diabetic neuropathy, duloxetine is an antidepressant that has shown benefit in the management of neuropathic pain [11,12]. Local anesthetics, in the form of a transdermal patch, and topical capsaicin may be useful for treating localized somatic pain [10,11]. Metastatic or primary bone pain may be treated with bisphosphonates, calcitonin, radionuclide and monoclonal antibodies, such as denosumab [10,13]. Pain related to spasticity may be treated with baclofen and benzodiazepines [11]. The second and third steps of the WHO analgesic ladder incorporate opioids into the management of cancer pain. Step two includes the use of weak opioids, such as codeine, tramadol, hydrocodone, and low dose oxycodone, morphine and hydromorphone for the treatment of mild-to-moderate pain [14,15]. The clinical use of ‘weak opiates’, as described in step two of the WHO analgesic ladder, has been challenged in more recent literature. Multiple studies have shown little analgesic benefit in the transition from step one to two and possible associated delay in achieving optimal pain control [16,17]. Step three opioids include higher doses and novel preparations of morphine, oxycodone, hydromorphone, oxymorphone and fentanyl, and their use is supported by the literature [18]. Numerous guidelines are available for deciding the use of opioids in cancer-pain patients [19]. For patients in whom the oral route of administration may not be convenient, fentanyl and buprenorphine are available as a transdermal patch [14]. Methadone can be a useful analgesic for patients with refractory cancer-pain syndromes. It can be administered when opioid rotation is indicated and when other opioids have lost their efficacy [20]. We advocate for the management of a patient’s clinical needs with respect to their subjective level of pain. Patients with severe pain on initial presentation, for example, should be managed with a medication and interventional approach that is concordant to the level of pain.
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Treatment strategies for cancer pain with a focus on interventional strategies
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Table 1. Nonopioid analgesics and adjuvants for cancer-pain management. Drug class
Mechanism of action
Nonsteroidal anti-inflammatory drugs Acetaminophen
Inhibit synthesis of prostaglandins from arachidonic acid by reversibly inhibiting COX-1 and -2 enzymes Inhibits synthesis of prostaglandins in the CNS and works peripherally to block pain impulse generation In a tissue-specific manner, corticosteroids regulate gene expression subsequent to the binding of specific intracellular receptors and translocation into the nucleus. They decrease inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability Increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of their reuptake by the presynaptic neuronal membrane. Additional effects may include desensitization of adenyl cyclase, downregulation of b-adrenergic receptors and downregulation of serotonin receptors Inhibit neuronal serotonin and norepinephrine reuptake and may weakly inhibit dopamine reuptake Block the initiation and conduction of nerve impulses by decreasing the neuronal membrane’s permeability to sodium ions, resulting in the inhibition of depolarization and the blocking of nerve conduction TRPV1 agonist that activates TRPV1 ligand-gated cation channels on nociceptive nerve fibers, resulting in depolarization, initiation of action potential and pain signal transmission to the spinal cord; exposure to capsaicin results in desensitization of the sensory axons and inhibition of pain transmission initiation For bone pain; they inhibit bone resorption via actions on osteoclasts or their precursors and decrease the rate of bone resorption, leading to an indirect increase in bone mineral density For bone pain; it functionally antagonizes the effects of parathyroid hormone and directly inhibits osteoclastic bone resorption Inhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticity Enhance the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, thus causing hyperpolarization and a less excitable state
Corticosteroids
Tricyclic antidepressants
Serotonin norepinephrine reuptake inhibitors Local anesthetics
Capsaicin
Bisphosphonates
Calcitonin Baclofen
Benzodiazepines
Data taken from [10,11].
Interventional management Interventional therapies targeting the neural mechanisms involved in cancer pain are an important alternative and adjunctive option in cancer-pain therapy. They have traditionally been considered when opioids and analgesic adjuvants do not give appropriate or sustained relief or have inhibiting side effects [21]. However, early evaluation for interventional therapy is also now advocated, even while initiating pharmacological treatment, and a continuum of treatment exists between interventional and pharmacological therapy [5]. Interventional strategies to control pain are not an alternative when pharmacologic treatment
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has ‘failed’. Several studies have shown the benefit of interventional procedures to treat pain in comparison to systemic opiate therapy [22–24]. Interventional approaches should be employed at all steps of patient presentation with cancerrelated pain and used in conjunction with pharmacological management. Interventional management for cancerrelated pain is generally grouped into two broad categories; peripheral and neuraxial. Peripheral therapies are used to modulate pain from specific nerves or groups of nerves, while neuraxial therapies can be employed in the epidural or intrathecal space. While not the primary focus of this article, performing some interventional
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai procedures may have potential risks to the patient. Experienced practitioners should be aware of these risks and monitor patients accordingly. Some potential risks of certain procedures will be discussed in the subsections of this article. Peripheral targets Non-neuraxial procedures involve precise modulation of peripheral and sympathetic nerves involved in afferent somatic pain signals, or sympathetic and visceral afferent pathways. Diagnostic and temporary relief of peripheral nerves and sympathetic fibers can be achieved with local anesthetics. Sustained relief may be achieved by steroid and local anesthetic deposition, cryotherapy, radiofrequency ablation or pulse, or neurolytic chemicals (i.e., phenol and alcohol) [25]. Peripheral nerves
The growth of a primary tumor, or metastases, may lead to significant somatic pain. Targeted nerve blocks can be employed to specific nerves involved in regions of disease burden. These procedures are effective when pain is limited to distribution of specific nerves, but may be limited by their duration of effect, deafferentation pain, and the possibility of sensory and motor deficits with neurolysis. Image guidance with ultrasound, fluoroscopy and computed tomography (CT) is commonly used to ensure accuracy and potentially limit complications. Examples
of common target nerves include the trigeminal nerve branches, sphenopalatine ganglion (parasympathetic mediated), brachial, lumbar and sacral plexus, intercostal nerves, ilioinguinal and iliohypogastric nerves, saphenous, and pudendal nerves. For example, if a tumor is located along a path of the intercostal nerve, such as a pleural based tumor, the intercostal nerve can be a target for neurolysis (Figure 1). Sympathetic nerves
The sympathetic nervous system can be involved in transmitting pain signals from cancer involving the viscera, primarily the abdominal and pelvic cavity. Local and regional sympathetic blockade can be used both to diagnose and treat sympathetically-mediated pain by interrupting sympathetic activity. Sympathetic system neurolysis interrupts efferent sympathetic fibers and afferent pain fibers traveling within the sympathetic chain [26,27]. Additionally, somatic-related pain, such as in the extremities, can be mediated with sympathetic blockade [28]. While sympathetic blocks may commonly be indicated for nonmalignant pain, they have found utility in treatments for cancer patients as well. Stellate ganglion block
The stellate ganglion is formed by the fusion of the inferior cervical sympathetic ganglion and the first thoracic sympathetic ganglion. It is involved in the sympathetic innervation of the head, neck, upper extremities and a portion of
†
Figure 1. Pharmacologic options for cancer-pain management. (A) Shown are the target rib and the location of the intercostal nerve below the rib under fluoroscopic guidance. (B) CT scan slice of thorax and lung field; the tumor is shown at the corresponding rib, which may be the cause of the patient’s pain (note: the patient has a history of mesothelioma with posterior chest wall pain). † The location of the tumor.
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Treatment strategies for cancer pain with a focus on interventional strategies
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Figure 2. Anterior–posterior and lateral views of a stellate ganglion block performed under fluoroscopic guidance, with dye showing spread along the longus colli muscle at C7. The patient is a 70-year-old male with sarcoma of the left brachial plexus, who presented with significant hand pain. Weekly stellate ganglion blocks allowed the patient to tolerate the radiation therapy and subsequent occupational therapy. (A) Anterior–posterior fluoroscopic view. (B) Lateral fluoroscopic view.
the upper thorax. Indications for cancer patients include phantom limb pain, neuropathic pain of the upper extremity and torso (usually from breast, thoracic and head/neck malignancy), postherpetic pain, postradiation pain, postsurgical neuropathy and atypical neuropathic facial pain [28]. Particular efficacy for the treatment of postmastectomy pain and hot flushes has been shown using this block technique [29,30]. Visual guidance under CT or ultrasound guidance can help a practitioner guide a needle to the anterior portion of the vertebral body at either C6 or C7 (Figure 2) [28]. After adequate block with local anesthetic, patients are monitored for postprocedural development of Horner syndrome (ptosis, miosis, conjunctival injection, ipsilateral facial warmth, anhidrosis and ipsilateral vasodilatation), which may indicate adequate block [28]. Despite adequate block, however, inability to block sympathetic fibers lying outside the trunk may limit pain relief [28]. Celiac plexus block
Innervation of the abdominal and pelvic viscera involves nerves that originate from T5–L1 preganglionic sympathetic fibers, forming the greater (T–T10), lesser (T10–T12), and least (T12–L1) splanchnic nerves [31]. These splanchnic groups unite to form a group of plexuses involved in abdominal and pelvic pain – the celiac plexus, superior hypogastric plexus and ganglion impar [6]. The celiac plexus is located underneath the
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diaphragmatic crus in the retroperitoneal space, and between the celiac and superior mesenteric arteries as they arise from the aorta. The most common indication for celiac plexus block is the management of pain from intraabdominal malignancy, typically pancreatic cancer [32,33]. Blockade of the celiac plexus has shown improvement in pain and quality of life, and reduction in systemic opioids [32,33]. Other indications include pain that may arise from the liver, gallbladder, stomach, spleen, kidneys, intestines and adrenals [31]. Typically, the procedure is performed with either fluoroscopic or CT guidance and in the prone position. Under CT guidance, if variation in patient anatomy does not allow for placement of a needle in the transcrural position adjacent to the aorta, the needle can be placed retrocrural, posterior to the aorta [34]. In the retrocural position, the targets of neurolysis are the splanchnic nerves (Figure 3). After neurolysis of the celiac plexus, patients can express transient effects of sympathetic blockade, orthostatic hypotension from vasodilation and diarrhea from unopposed parasympathetic activity. Complications include hematuria, intravascular injection, pneumothorax, and injury to the nerve root or dural cuff [35]. Lumbar sympathetic block
The lumbar sympathetic chain lies at the anterolateral border of the vertebral bodies and generally consists of two to six interconnected ganglia.
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Figure 3. Computed tomography-guided celiac plexus block at the level of L1. The patient has a history of pancreatic cancer with chronic epigastric pain. The left needle is in the transcrural position, while the right needle is in the retrocrural position. The needle position is confirmed with computed tomography and contrast dye spread.
The ganglia are located primarily along the L2 and L3 vertebral bodies [36,37]. Lumbar sympathetic block is indicated for complex regional pain syndrome I and II, peripheral neuropathy pain, ischemia-related pain, and cancer pain stemming from abdominal and pelvic organs [37,38]. Lumbar sympathetic block has also been shown to help treat cancer-related bladder spasm [35]. Commonly, fluoroscopy or CT imaging can be used to guide the needle to the anterolateral border of the lumbar spine, and contrast is used to confirm the spread of medication along the
anterior and lateral borders of the vertebral bodies (Figure 4). If long-lasting results are not obtained with local anesthetic blockade, chemical neurolysis may be considered, although this may risk somatic nerve injury. Radiofrequency stimulation may be used to diffrentiate the splanchnic nerves (which supply the pelvic viscera) from the lumbar sympathetic change (which supply the lower extremity), allowing for specific targeting for neurolytic treatments [36]. Common side effects of this block include hypotension secondary to vasodilatation from decreased sympathetic activity. Complications from blockade and/or neurolysis include bleeding, nerve root injury, genitofemoral neuritis/neuralgia, paralysis, neuraxial injection and renal puncture or trauma [37]. Superior hypogastric plexus block
The superior hypogastric plexus is the lower continuation of the inferior mesenteric plexus. It contains postganglionic sympathetic and afferent visceral pain nerve fibers. Nerve fibers from the superior hypogastric plexus cover a wide area over the ventral surface of the lower lumbar vertebrae, focused largely left of midline at the L5/S1 junction [26]. The bifurcation of the aorta into the common iliac vessels occurs close to the superior hypogastric plexus (Figure 5). For visceral pain originating from the pelvic organs, the superior hypogastric plexus block may be an effective treatment
Figure 4. Fluoroscopic guided lumbar sympathetic block at L4. Both the anterior–posterior and lateral views show good contrast spread along the anterolateral border of L4 and L3, with no muscular, intravenous or arterial spread. The patient has a history of bladder cancer treatment-related pain, which improved after repetitive treatments. (A) Lateral fluoroscopic view. (B) Anterior–posterior fluoroscopic view.
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Treatment strategies for cancer pain with a focus on interventional strategies option [26,37]. Performing this procedure early may reduce opioid use [39]. Fluoroscopy (ultrasound or CT scan) can be used with a bilateral approach at the L5 or L5–S1 junction to guide the needles to target, and contrast is used to confirm spread over the anterolateral surface of the vertebral body without posterior spread towards exiting nerve roots. If the diagnostic block results in significant improvement in pain, neurolysis can be performed with alcohol or phenol. Potential complications of the block include bleeding, bruising, infection, local anesthetic toxicity, damage/irritation to nerve structures, sexual dysfunction, intraperitoneal and intramuscular injection, and visceral injury [39].
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Lumbar sympathetic chain
Aorta L1
L2
Lumbar splanchnic nerves
Transverse process
L3 Spinal nerve L4
Target injection area
Ganglion of impar
The ganglion of impar is the inferior, distal termination of the paired sympathetic chains. It contains the postganglionic sympathetic fibers, in addition to afferent pain fibers. It is typically located on the ventral aspect of the sacrococcygeal junction, although it may also be found distally, ventral to the coccyx. The presacral (ganglion of impar) block is indicated for refractory pelvic and perineal pain for cancers of the pelvic organs [37,39]. The ganglion of impar block is performed with the patient in the prone position. Using fluoroscopy, the needle is advanced through the sacrococcygeal ligament in the lateral view until the needle tip is anterior to the ventral sacrococcygeal ligament (Figure 6). Contrast is used to confirm spread on the ventral aspect of the sacrum and coccyx. If the diagnostic block results in improvement of pain, neurolysis can be performed with alcohol or phenol [39]. Complications may include bleeding, infection, rectal or muscular damage [39]. Neuraxial Neuraxial management of cancer-related pain focuses on direct modulation of afferent nociceptive fibers, interneurons and ascending fibers of the spinal cord. Epidural and intrathecal use of analgesic agents (opioids, steroids, local anesthetic and adjuvants) can provide significant pain relief with fewer side effects than oral or parenteral opiates [40–44]. Further discussion and evaluation of the literature regarding the benefits of intrathecal medications are discussed in this section. Epidural injection of steroid or chemical neurolytics is often employed for tumor
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L5
Superior hypogastric plexus
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Figure 5. Image signifying the branches of the splanchnic nerves and the formation of the superior hypogastric plexus. The plexus surrounds the iliac vessels in the area of L5 and S1. Illustrated is the target for the lumbar splanchnic nerves.
extension that may involve spinal nerve roots [44]. Neuromodulation, including transcutaneous electric nerve stimulation and spinal cord stimulation, may provide significant relief for cancer-pain patients (Figure 7). While beneficial, electrical stimulation will only be referenced in this article [45–47]. Tunneled epidural catheters and intrathecal pumps are commonly employed for refractory pain [48,49]. Intrathecal neurolysis
For patients with intractable malignant pain in a focal area, intrathecal neurolysis may be a viable option for pain control [44]. These techniques tend to be reserved for patients with a poor prognosis and short life expectancy. The pain may recur after these techniques in a few months and significant side effects (bladder and rectal sphincter dysfunction) may occur [50] . Both alcohol and phenol are common agents and require significant expertise when the medication is deposited in the intrathecal space [51].
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Figure 6. Shown are lateral and anterior–posterior views of a cryoprobe inserted at the intercoccygeal ligament in search of the ganglion of impar. The patient has a history of rectal pain and burning, which was relieved with cryoablation of the ganglion of impar. Intrathecal drug delivery
For cancer patients who are unable to obtain adequate pain control with systemic medications, or have pain that is not treatable with nerve blocks of the central axis, autonomic nervous system or peripheral nerves, the delivery of medication by the intrathecal route may prove beneficial. For many patients in the late stages of their disease, when pain becomes severe, the dose of opioids required for adequate pain relief may cause unacceptable side effects, such as extreme sedation, confusion, nausea, vomiting and constipation. The pain may become increasingly difficult to manage and many patients suffer greatly. Intrathecal administration of opioids has been shown in multiple studies to be extremely effective and nonsedating [52]. The placement of a subcutaneous reservoir of opioids that is delivered by a pump to the intrathecal space allows patients with intractable pain secondary to cancer to lead a more comfortable life [53]. Compared with intravenous opioid use, opioids delivered by the intrathecal route can be up to 100 times more potent. For example, 10 mg of intravenous morphine may have the same effect as 0.1 mg of intrathecal morphine [54]. Intrathecal analgesia has been shown to decrease refractory cancer pain from 86 to 17% in an 8-week follow-up period [52]. Morphine remains the gold standard for intrathecal analgesia because of its long history of use, duration of action and ease of use. However, a wide variety of drugs can be used in combination for intrathecal analgesia, including hydromorphone, fentanyl,
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bupivacaine, ziconotide, clonidine, sufentanil, ropivacaine, buprenorphine, midazolam, meperidine and ketorolac. Experimental agents that have been used intrathecally include gabapentin, octreotide, conopeptide, neostigmine and adenosine [53,54]. The use of intrathecal medications, especially opioids, has been shown to reduce toxicity and, in some cases, improve survival compared with patients receiving conventional medical management [55]. However, the use of each individual medication presents risks to patients. For example, intrathecal clonidine may be sedating, baclofen can cause a fatal withdrawal syndrome and ziconotide may lead to altered mental status [56–58]. A recent consensus conference has published recommendations regarding maximum dosage, trialing and choice of intrathecal pump medications, which can be referred to when deciding intrathecal drug choices [59,60]. Visceral nociceptive pain from pancreatic, liver and stomach carcinoma, and somatic nociceptive pain from bone metastases have been effectively treated with intrathecal analgesia. Intrathecal analgesia may also treat neuropathic pain, such as that seen with postherpetic neuralgia or cancerrelated plexopathies. Pain syndromes stemming from a combination of neuropathic and nociceptive pain mechanisms may be the most difficult to treat and may require combination therapy to provide effective analgesia [54]. Prior to placement of a permanent intrathecal pump, a trial is generally performed to determine patient response to therapy and to assist in
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Treatment strategies for cancer pain with a focus on interventional strategies selection of the most appropriate medications and dosage. Trialing can be done using a single injection, multiple injections or continuous infusions, either into the epidural or intrathecal space [53,59]. A trial is usually considered positive when there is a greater than 50% reduction in pain intensity, although guidelines are available regarding this [59]. After a positive trial, options for intrathecal drug delivery systems may include percutaneous short-term intrathecal catheters, long-term tunneled intrathecal catheters, and fully-implantable infusion pump and catheter systems. For a patient with a life expectancy of less than 3 months, a percutaneous external system may be more appropriate [101]. For patients with a fully implantable pump and catheter, pumps require periodic scheduled refilling and reprogramming. The interval of refill depends on the drug reservoir volume (20 or 40 ml), drug dose, concentration and stability. The intrathecal pump must be refilled using an aseptic technique, as it is contiguous with the intrathecal space. Telemetry is used to check the pump model, reservoir size, and to adjust settings and determine refill date. A patient-controlled device that allows for self-administered boluses may improve quality of life in these patients [61]. A
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Vertebroplasty & kyphoplasty
Vertebroplasty and kyphoplasty are interventional procedures that have been developed to manage pain from vertebral collapse that results from osteoporosis or malignant disease. The technique of vertebroplasty, which involves the transpedicular delivery of polymethylmethacrylate, was initially developed for the treatment of spinal hemangiomas. The objective is primarily to provide pain relief, although the procedures also have the perpetrated benefit of vertebral stability by inhibiting the progression of fracture and further vertebral body collapse [62]. In determining appropriate candidates for vertebroplasty or kyphoplasty, physical examination and diagnostic imaging, including bone scan and MRI or CT scan, should be used to rule out other causes of back pain (i.e., facet disease or nerve compression). The patient’s pain symptoms should correspond to the level of vertebral fracture. Bone scans are helpful in determining the age of fracture, with more recent fractures corresponding to more effective pain relief from the procedure [62,63]. MRI is also used to determine age of fracture and evaluate any additional pathology that may contribute to pain. Front view
B
Back view
TENS
B
B Right
B Left
Left
Right
Figure 7. Neuromodulation techniques for treating cancer-related pain syndromes. (A) Patient with history of testicular cancer with neuropathic pain of the left testis and groin. A 16-lead spinal cord stimulator was placed in the epidural space to stimulate the dorsal columns at T6 with thoracic nerve roots stimulated at T10. (B) Diagram showing placement of TENS unit pads for patient with sacral sarcoma. Patient was able to use TENS unit to increase his ability to ambulate as part of goal-directed therapy. B: External and internal pain; TENS: Transcutaneous electric nerve stimulation.
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai Fractures with a greater than 80% loss of vertebral body height do not respond well to vertebroplasty and kyphoplasty [62], although there are limited series of patients with severe fractures that have shown improvement [64]. Contraindications include retropulsed bone fragment, involvement of malignancy in the epidural space, poorly localized pain, infection and patients’ inability to lay prone [62]. In addition to damage to neural and vascular structures when accessing the vertebral body, adverse effects of vertebroplasty and kyphoplasty include extravasation of cement, which may cause pressure on spinal cord and nerve roots, cement embolization and pulmonary embolization. Infection is a rare, but serious, complication. Two highly publicized randomized studies published in 2009 evaluated the use of vertebroplasty for painful osteoporotic vertebral fractures. Both studies failed to show reduced pain over the control [65,66]. There is limited evidence to suggest benefit from vertebroplasty and kyphoplasty in patients with vertebral body fractures secondary to malignancy. There are two prospective uncontrolled trials showing pain relief from vertebroplasty and kyphoplasty in patients with pathologic vertebral body fractures secondary to malignancy [67,68]. Additionally, one randomized controlled trial shows balloon kyphoplasty to be superior to nonsurgical management for cancer-related vertebral compression fractures [69]. Conclusion Various techniques are available for interventional management of cancer pain. The current literature supports the use of interventional procedures as an adjunct to pharmacologic management for cancer-related pain symptoms. While the majority of cancer-pain patients may have their pain symptoms controlled with References
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pharmacologic treatments, modulation of the sympathetic chain, peripheral nerve targets and intrathecal space is a growing discipline in cancer-pain management. A continuum now exists in the treatment of oncologic pain such that interventions may be offered at any point of a cancer patient’s pain treatment plan. Future perspective As our treatments for cancer improve, various cancers will be viewed as a chronic disease. As such, chronic pharmacologic treatments (especially those focusing on opioid management) may be insufficient in managing pain. Further work will need to be done to understand when and how to apply interventional procedures as part of a new paradigm in managing these patients. On the horizon are ultrasound guided techniques for nerve blockade and further use of neuromodulation, such as transcutaneous electric nerve stimulation, peripheral and spinal cord stimulation. These new techniques and new technologies that are applied to chronic noncancer-pain patients will have to be evaluated for their efficacy in the cancer-pain population. Further insight and research will lead to increased use of interventional techniques as part of a continuum during and after cancer patient’s oncologic treatment. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth. Analg. 106(2), 628–637 (2008).
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delivery system for cancer pain management: a review and updates. Am. J. Hospice Palliat. Med. 29(5), 388–398 (2012). 54 de Leon-Casasola OA. Interventional
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An overview of treatment strategies for cancer pain with a focus on interventional strategies and techniques
Practice Points
Amitabh Gulati*1, Jatin Joshi2 & Aisha Baqai2 Patients suffering from cancer-related pain syndromes have many pharmacologic options in
alleviating their specific symptoms. Interventional techniques in cancer-pain management are increasingly becoming part of the
continuum of treating a cancer patient’s pain. The sympathetic system is an important target for treatment of a cancer patient’s pain
syndrome. With newer imaging techniques, such as ultrasonography, peripheral nerves can be accurately
targeted for treatment of peripheral cancer-pain syndromes. Intrathecal drug delivery remains a vital technique in assisting patients with focal areas of pain
and the devices allow for delivery of medications that cannot be safely given systemically for pain control.
SUMMARY As the incidence of cancer increases, considerations for pain treatments become more important and varied. While traditional views on pain therapy are successful in treating the majority of cancer-related pain, a continuum has developed to include interventional strategies in addition to pharmacologic management. Further improvements in understanding anatomy in the context of imaging and pathophysiology of cancer-pain syndromes direct our current interventional pain management options. We discuss the current interventional treatment options regularly used in the cancer-pain population. Cancer affects more than a million people a year in the USA, and is the second leading cause of mortality [1]. In the advanced stages of cancer, pain is prevalent in 70–90% of patients, although less than half of patients get adequate pain relief [2]. Accordingly, pain is one of the major fears of cancer patients and significantly affects quality of life, coping mechanisms and the burden of the disease [3].
While up to 90% of cancer-related pain can be managed with basic pain management techniques focused on opioid medications, the remaining patients may benefit from alternative treatments [4]. Management of uncontrolled pain may be treated with chemotherapy, radiation therapy and surgical options. However, interventional pain therapies are available to improve both pain control and quality of life
Department of Anesthesiology & Critical Care, Board Certified in Anesthesiology & Pain Management, Memorial Sloan Kettering Cancer Center, M308, New York, NY, 10065, USA 2 Department of Anesthesiology, Weill Medical College, Cornell University, New York, NY, USA *Author for correspondence: Tel.: +1 212 639 6851; Fax: +1 212 717 3206; [email protected] 1
10.2217/PMT.12.61 © 2012 Future Medicine Ltd
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai in cancer patients with uncontrolled pain [5]. While pharmacologic therapy, primarily opioid and adjuvant medications, remains the mainstay for pain therapy, interventional approaches can serve as valuable modalities and adjuncts for pain management. Many nonpharmacologic techniques have been investigated for the management of cancer pain and resulting comorbidities including insomnia, depression and anxiety. However, in this article we aim to introduce the reader to various interventional techniques that are commonly offered to patients suffering with cancer-related pain. This is not an exhaustive list and some topics are only introduced and not comprehensively discussed. While risks and side effects of these procedures are not discussed in detail, some references are provided for the reader to refer to in the literature. We will also briefly discuss pharmacologic management options for these patients and add references for the reader regarding noninterventional treatment algorithms. Pharmacological management Cancer can cause pain that is somatic, visceral, referred or neuropathic in origin. For instance, back pain is a referred pain that is frequently seen with pancreatic cancer. Lesions of the nervous system may lead to neuropathic pain complaints, such as plexopathies from metastatic disease compressing the nerve bundle [6]. These different pain generators can be targeted by specific pharmacologic treatments. It is common for cancer patients to receive multimodal pharmacologic treatment for better pain control. Most cancer patients may be adequately treated with pharmacological methods and these are discussed briefly below. Introduced in 1986, the WHO ladder is a validated method of addressing pharmacologic management of cancer pain. Although no fourth step has been added formally to the classification system, interventional therapies can be used at any step in pain management [7]. Studies have supported the paradigm’s efficacy in relieving cancer-related pain; however, data suggests that adherence to the analgesic ladder and other pain guidelines are not consistent [8]. The first step of the WHO analgesic ladder includes nonopioid analgesics and adjuvant medications; however, these may be more effective in combination [9]. Because the etiology of cancer pain is complex, properties of various medications can target many different
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pain mechanisms (Table 1). Nonsteroidal antiinflammatory drugs, COX-2 inhibitors, acetylsalicylic acid, intravenous acetaminophen and corticosteroids target inflammation caused by cancers [10]. Adjuvant medications, such as antidepressants (e.g., nortriptyline) and anticonvulsants (e.g., gabapentin and pregabalin), are used to target neuropathic pain related to cancer [10,11]. Although only formally indicated to manage pain from fibromyalgia and peripheral diabetic neuropathy, duloxetine is an antidepressant that has shown benefit in the management of neuropathic pain [11,12]. Local anesthetics, in the form of a transdermal patch, and topical capsaicin may be useful for treating localized somatic pain [10,11]. Metastatic or primary bone pain may be treated with bisphosphonates, calcitonin, radionuclide and monoclonal antibodies, such as denosumab [10,13]. Pain related to spasticity may be treated with baclofen and benzodiazepines [11]. The second and third steps of the WHO analgesic ladder incorporate opioids into the management of cancer pain. Step two includes the use of weak opioids, such as codeine, tramadol, hydrocodone, and low dose oxycodone, morphine and hydromorphone for the treatment of mild-to-moderate pain [14,15]. The clinical use of ‘weak opiates’, as described in step two of the WHO analgesic ladder, has been challenged in more recent literature. Multiple studies have shown little analgesic benefit in the transition from step one to two and possible associated delay in achieving optimal pain control [16,17]. Step three opioids include higher doses and novel preparations of morphine, oxycodone, hydromorphone, oxymorphone and fentanyl, and their use is supported by the literature [18]. Numerous guidelines are available for deciding the use of opioids in cancer-pain patients [19]. For patients in whom the oral route of administration may not be convenient, fentanyl and buprenorphine are available as a transdermal patch [14]. Methadone can be a useful analgesic for patients with refractory cancer-pain syndromes. It can be administered when opioid rotation is indicated and when other opioids have lost their efficacy [20]. We advocate for the management of a patient’s clinical needs with respect to their subjective level of pain. Patients with severe pain on initial presentation, for example, should be managed with a medication and interventional approach that is concordant to the level of pain.
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Treatment strategies for cancer pain with a focus on interventional strategies
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Table 1. Nonopioid analgesics and adjuvants for cancer-pain management. Drug class
Mechanism of action
Nonsteroidal anti-inflammatory drugs Acetaminophen
Inhibit synthesis of prostaglandins from arachidonic acid by reversibly inhibiting COX-1 and -2 enzymes Inhibits synthesis of prostaglandins in the CNS and works peripherally to block pain impulse generation In a tissue-specific manner, corticosteroids regulate gene expression subsequent to the binding of specific intracellular receptors and translocation into the nucleus. They decrease inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability Increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of their reuptake by the presynaptic neuronal membrane. Additional effects may include desensitization of adenyl cyclase, downregulation of b-adrenergic receptors and downregulation of serotonin receptors Inhibit neuronal serotonin and norepinephrine reuptake and may weakly inhibit dopamine reuptake Block the initiation and conduction of nerve impulses by decreasing the neuronal membrane’s permeability to sodium ions, resulting in the inhibition of depolarization and the blocking of nerve conduction TRPV1 agonist that activates TRPV1 ligand-gated cation channels on nociceptive nerve fibers, resulting in depolarization, initiation of action potential and pain signal transmission to the spinal cord; exposure to capsaicin results in desensitization of the sensory axons and inhibition of pain transmission initiation For bone pain; they inhibit bone resorption via actions on osteoclasts or their precursors and decrease the rate of bone resorption, leading to an indirect increase in bone mineral density For bone pain; it functionally antagonizes the effects of parathyroid hormone and directly inhibits osteoclastic bone resorption Inhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticity Enhance the inhibitory effect of GABA on neuronal excitability by increasing neuronal membrane permeability to chloride ions, thus causing hyperpolarization and a less excitable state
Corticosteroids
Tricyclic antidepressants
Serotonin norepinephrine reuptake inhibitors Local anesthetics
Capsaicin
Bisphosphonates
Calcitonin Baclofen
Benzodiazepines
Data taken from [10,11].
Interventional management Interventional therapies targeting the neural mechanisms involved in cancer pain are an important alternative and adjunctive option in cancer-pain therapy. They have traditionally been considered when opioids and analgesic adjuvants do not give appropriate or sustained relief or have inhibiting side effects [21]. However, early evaluation for interventional therapy is also now advocated, even while initiating pharmacological treatment, and a continuum of treatment exists between interventional and pharmacological therapy [5]. Interventional strategies to control pain are not an alternative when pharmacologic treatment
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has ‘failed’. Several studies have shown the benefit of interventional procedures to treat pain in comparison to systemic opiate therapy [22–24]. Interventional approaches should be employed at all steps of patient presentation with cancerrelated pain and used in conjunction with pharmacological management. Interventional management for cancerrelated pain is generally grouped into two broad categories; peripheral and neuraxial. Peripheral therapies are used to modulate pain from specific nerves or groups of nerves, while neuraxial therapies can be employed in the epidural or intrathecal space. While not the primary focus of this article, performing some interventional
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai procedures may have potential risks to the patient. Experienced practitioners should be aware of these risks and monitor patients accordingly. Some potential risks of certain procedures will be discussed in the subsections of this article. Peripheral targets Non-neuraxial procedures involve precise modulation of peripheral and sympathetic nerves involved in afferent somatic pain signals, or sympathetic and visceral afferent pathways. Diagnostic and temporary relief of peripheral nerves and sympathetic fibers can be achieved with local anesthetics. Sustained relief may be achieved by steroid and local anesthetic deposition, cryotherapy, radiofrequency ablation or pulse, or neurolytic chemicals (i.e., phenol and alcohol) [25]. Peripheral nerves
The growth of a primary tumor, or metastases, may lead to significant somatic pain. Targeted nerve blocks can be employed to specific nerves involved in regions of disease burden. These procedures are effective when pain is limited to distribution of specific nerves, but may be limited by their duration of effect, deafferentation pain, and the possibility of sensory and motor deficits with neurolysis. Image guidance with ultrasound, fluoroscopy and computed tomography (CT) is commonly used to ensure accuracy and potentially limit complications. Examples
of common target nerves include the trigeminal nerve branches, sphenopalatine ganglion (parasympathetic mediated), brachial, lumbar and sacral plexus, intercostal nerves, ilioinguinal and iliohypogastric nerves, saphenous, and pudendal nerves. For example, if a tumor is located along a path of the intercostal nerve, such as a pleural based tumor, the intercostal nerve can be a target for neurolysis (Figure 1). Sympathetic nerves
The sympathetic nervous system can be involved in transmitting pain signals from cancer involving the viscera, primarily the abdominal and pelvic cavity. Local and regional sympathetic blockade can be used both to diagnose and treat sympathetically-mediated pain by interrupting sympathetic activity. Sympathetic system neurolysis interrupts efferent sympathetic fibers and afferent pain fibers traveling within the sympathetic chain [26,27]. Additionally, somatic-related pain, such as in the extremities, can be mediated with sympathetic blockade [28]. While sympathetic blocks may commonly be indicated for nonmalignant pain, they have found utility in treatments for cancer patients as well. Stellate ganglion block
The stellate ganglion is formed by the fusion of the inferior cervical sympathetic ganglion and the first thoracic sympathetic ganglion. It is involved in the sympathetic innervation of the head, neck, upper extremities and a portion of
†
Figure 1. Pharmacologic options for cancer-pain management. (A) Shown are the target rib and the location of the intercostal nerve below the rib under fluoroscopic guidance. (B) CT scan slice of thorax and lung field; the tumor is shown at the corresponding rib, which may be the cause of the patient’s pain (note: the patient has a history of mesothelioma with posterior chest wall pain). † The location of the tumor.
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Treatment strategies for cancer pain with a focus on interventional strategies
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Figure 2. Anterior–posterior and lateral views of a stellate ganglion block performed under fluoroscopic guidance, with dye showing spread along the longus colli muscle at C7. The patient is a 70-year-old male with sarcoma of the left brachial plexus, who presented with significant hand pain. Weekly stellate ganglion blocks allowed the patient to tolerate the radiation therapy and subsequent occupational therapy. (A) Anterior–posterior fluoroscopic view. (B) Lateral fluoroscopic view.
the upper thorax. Indications for cancer patients include phantom limb pain, neuropathic pain of the upper extremity and torso (usually from breast, thoracic and head/neck malignancy), postherpetic pain, postradiation pain, postsurgical neuropathy and atypical neuropathic facial pain [28]. Particular efficacy for the treatment of postmastectomy pain and hot flushes has been shown using this block technique [29,30]. Visual guidance under CT or ultrasound guidance can help a practitioner guide a needle to the anterior portion of the vertebral body at either C6 or C7 (Figure 2) [28]. After adequate block with local anesthetic, patients are monitored for postprocedural development of Horner syndrome (ptosis, miosis, conjunctival injection, ipsilateral facial warmth, anhidrosis and ipsilateral vasodilatation), which may indicate adequate block [28]. Despite adequate block, however, inability to block sympathetic fibers lying outside the trunk may limit pain relief [28]. Celiac plexus block
Innervation of the abdominal and pelvic viscera involves nerves that originate from T5–L1 preganglionic sympathetic fibers, forming the greater (T–T10), lesser (T10–T12), and least (T12–L1) splanchnic nerves [31]. These splanchnic groups unite to form a group of plexuses involved in abdominal and pelvic pain – the celiac plexus, superior hypogastric plexus and ganglion impar [6]. The celiac plexus is located underneath the
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diaphragmatic crus in the retroperitoneal space, and between the celiac and superior mesenteric arteries as they arise from the aorta. The most common indication for celiac plexus block is the management of pain from intraabdominal malignancy, typically pancreatic cancer [32,33]. Blockade of the celiac plexus has shown improvement in pain and quality of life, and reduction in systemic opioids [32,33]. Other indications include pain that may arise from the liver, gallbladder, stomach, spleen, kidneys, intestines and adrenals [31]. Typically, the procedure is performed with either fluoroscopic or CT guidance and in the prone position. Under CT guidance, if variation in patient anatomy does not allow for placement of a needle in the transcrural position adjacent to the aorta, the needle can be placed retrocrural, posterior to the aorta [34]. In the retrocural position, the targets of neurolysis are the splanchnic nerves (Figure 3). After neurolysis of the celiac plexus, patients can express transient effects of sympathetic blockade, orthostatic hypotension from vasodilation and diarrhea from unopposed parasympathetic activity. Complications include hematuria, intravascular injection, pneumothorax, and injury to the nerve root or dural cuff [35]. Lumbar sympathetic block
The lumbar sympathetic chain lies at the anterolateral border of the vertebral bodies and generally consists of two to six interconnected ganglia.
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Figure 3. Computed tomography-guided celiac plexus block at the level of L1. The patient has a history of pancreatic cancer with chronic epigastric pain. The left needle is in the transcrural position, while the right needle is in the retrocrural position. The needle position is confirmed with computed tomography and contrast dye spread.
The ganglia are located primarily along the L2 and L3 vertebral bodies [36,37]. Lumbar sympathetic block is indicated for complex regional pain syndrome I and II, peripheral neuropathy pain, ischemia-related pain, and cancer pain stemming from abdominal and pelvic organs [37,38]. Lumbar sympathetic block has also been shown to help treat cancer-related bladder spasm [35]. Commonly, fluoroscopy or CT imaging can be used to guide the needle to the anterolateral border of the lumbar spine, and contrast is used to confirm the spread of medication along the
anterior and lateral borders of the vertebral bodies (Figure 4). If long-lasting results are not obtained with local anesthetic blockade, chemical neurolysis may be considered, although this may risk somatic nerve injury. Radiofrequency stimulation may be used to diffrentiate the splanchnic nerves (which supply the pelvic viscera) from the lumbar sympathetic change (which supply the lower extremity), allowing for specific targeting for neurolytic treatments [36]. Common side effects of this block include hypotension secondary to vasodilatation from decreased sympathetic activity. Complications from blockade and/or neurolysis include bleeding, nerve root injury, genitofemoral neuritis/neuralgia, paralysis, neuraxial injection and renal puncture or trauma [37]. Superior hypogastric plexus block
The superior hypogastric plexus is the lower continuation of the inferior mesenteric plexus. It contains postganglionic sympathetic and afferent visceral pain nerve fibers. Nerve fibers from the superior hypogastric plexus cover a wide area over the ventral surface of the lower lumbar vertebrae, focused largely left of midline at the L5/S1 junction [26]. The bifurcation of the aorta into the common iliac vessels occurs close to the superior hypogastric plexus (Figure 5). For visceral pain originating from the pelvic organs, the superior hypogastric plexus block may be an effective treatment
Figure 4. Fluoroscopic guided lumbar sympathetic block at L4. Both the anterior–posterior and lateral views show good contrast spread along the anterolateral border of L4 and L3, with no muscular, intravenous or arterial spread. The patient has a history of bladder cancer treatment-related pain, which improved after repetitive treatments. (A) Lateral fluoroscopic view. (B) Anterior–posterior fluoroscopic view.
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Treatment strategies for cancer pain with a focus on interventional strategies option [26,37]. Performing this procedure early may reduce opioid use [39]. Fluoroscopy (ultrasound or CT scan) can be used with a bilateral approach at the L5 or L5–S1 junction to guide the needles to target, and contrast is used to confirm spread over the anterolateral surface of the vertebral body without posterior spread towards exiting nerve roots. If the diagnostic block results in significant improvement in pain, neurolysis can be performed with alcohol or phenol. Potential complications of the block include bleeding, bruising, infection, local anesthetic toxicity, damage/irritation to nerve structures, sexual dysfunction, intraperitoneal and intramuscular injection, and visceral injury [39].
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Lumbar sympathetic chain
Aorta L1
L2
Lumbar splanchnic nerves
Transverse process
L3 Spinal nerve L4
Target injection area
Ganglion of impar
The ganglion of impar is the inferior, distal termination of the paired sympathetic chains. It contains the postganglionic sympathetic fibers, in addition to afferent pain fibers. It is typically located on the ventral aspect of the sacrococcygeal junction, although it may also be found distally, ventral to the coccyx. The presacral (ganglion of impar) block is indicated for refractory pelvic and perineal pain for cancers of the pelvic organs [37,39]. The ganglion of impar block is performed with the patient in the prone position. Using fluoroscopy, the needle is advanced through the sacrococcygeal ligament in the lateral view until the needle tip is anterior to the ventral sacrococcygeal ligament (Figure 6). Contrast is used to confirm spread on the ventral aspect of the sacrum and coccyx. If the diagnostic block results in improvement of pain, neurolysis can be performed with alcohol or phenol [39]. Complications may include bleeding, infection, rectal or muscular damage [39]. Neuraxial Neuraxial management of cancer-related pain focuses on direct modulation of afferent nociceptive fibers, interneurons and ascending fibers of the spinal cord. Epidural and intrathecal use of analgesic agents (opioids, steroids, local anesthetic and adjuvants) can provide significant pain relief with fewer side effects than oral or parenteral opiates [40–44]. Further discussion and evaluation of the literature regarding the benefits of intrathecal medications are discussed in this section. Epidural injection of steroid or chemical neurolytics is often employed for tumor
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L5
Superior hypogastric plexus
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Figure 5. Image signifying the branches of the splanchnic nerves and the formation of the superior hypogastric plexus. The plexus surrounds the iliac vessels in the area of L5 and S1. Illustrated is the target for the lumbar splanchnic nerves.
extension that may involve spinal nerve roots [44]. Neuromodulation, including transcutaneous electric nerve stimulation and spinal cord stimulation, may provide significant relief for cancer-pain patients (Figure 7). While beneficial, electrical stimulation will only be referenced in this article [45–47]. Tunneled epidural catheters and intrathecal pumps are commonly employed for refractory pain [48,49]. Intrathecal neurolysis
For patients with intractable malignant pain in a focal area, intrathecal neurolysis may be a viable option for pain control [44]. These techniques tend to be reserved for patients with a poor prognosis and short life expectancy. The pain may recur after these techniques in a few months and significant side effects (bladder and rectal sphincter dysfunction) may occur [50] . Both alcohol and phenol are common agents and require significant expertise when the medication is deposited in the intrathecal space [51].
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai
Figure 6. Shown are lateral and anterior–posterior views of a cryoprobe inserted at the intercoccygeal ligament in search of the ganglion of impar. The patient has a history of rectal pain and burning, which was relieved with cryoablation of the ganglion of impar. Intrathecal drug delivery
For cancer patients who are unable to obtain adequate pain control with systemic medications, or have pain that is not treatable with nerve blocks of the central axis, autonomic nervous system or peripheral nerves, the delivery of medication by the intrathecal route may prove beneficial. For many patients in the late stages of their disease, when pain becomes severe, the dose of opioids required for adequate pain relief may cause unacceptable side effects, such as extreme sedation, confusion, nausea, vomiting and constipation. The pain may become increasingly difficult to manage and many patients suffer greatly. Intrathecal administration of opioids has been shown in multiple studies to be extremely effective and nonsedating [52]. The placement of a subcutaneous reservoir of opioids that is delivered by a pump to the intrathecal space allows patients with intractable pain secondary to cancer to lead a more comfortable life [53]. Compared with intravenous opioid use, opioids delivered by the intrathecal route can be up to 100 times more potent. For example, 10 mg of intravenous morphine may have the same effect as 0.1 mg of intrathecal morphine [54]. Intrathecal analgesia has been shown to decrease refractory cancer pain from 86 to 17% in an 8-week follow-up period [52]. Morphine remains the gold standard for intrathecal analgesia because of its long history of use, duration of action and ease of use. However, a wide variety of drugs can be used in combination for intrathecal analgesia, including hydromorphone, fentanyl,
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bupivacaine, ziconotide, clonidine, sufentanil, ropivacaine, buprenorphine, midazolam, meperidine and ketorolac. Experimental agents that have been used intrathecally include gabapentin, octreotide, conopeptide, neostigmine and adenosine [53,54]. The use of intrathecal medications, especially opioids, has been shown to reduce toxicity and, in some cases, improve survival compared with patients receiving conventional medical management [55]. However, the use of each individual medication presents risks to patients. For example, intrathecal clonidine may be sedating, baclofen can cause a fatal withdrawal syndrome and ziconotide may lead to altered mental status [56–58]. A recent consensus conference has published recommendations regarding maximum dosage, trialing and choice of intrathecal pump medications, which can be referred to when deciding intrathecal drug choices [59,60]. Visceral nociceptive pain from pancreatic, liver and stomach carcinoma, and somatic nociceptive pain from bone metastases have been effectively treated with intrathecal analgesia. Intrathecal analgesia may also treat neuropathic pain, such as that seen with postherpetic neuralgia or cancerrelated plexopathies. Pain syndromes stemming from a combination of neuropathic and nociceptive pain mechanisms may be the most difficult to treat and may require combination therapy to provide effective analgesia [54]. Prior to placement of a permanent intrathecal pump, a trial is generally performed to determine patient response to therapy and to assist in
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Treatment strategies for cancer pain with a focus on interventional strategies selection of the most appropriate medications and dosage. Trialing can be done using a single injection, multiple injections or continuous infusions, either into the epidural or intrathecal space [53,59]. A trial is usually considered positive when there is a greater than 50% reduction in pain intensity, although guidelines are available regarding this [59]. After a positive trial, options for intrathecal drug delivery systems may include percutaneous short-term intrathecal catheters, long-term tunneled intrathecal catheters, and fully-implantable infusion pump and catheter systems. For a patient with a life expectancy of less than 3 months, a percutaneous external system may be more appropriate [101]. For patients with a fully implantable pump and catheter, pumps require periodic scheduled refilling and reprogramming. The interval of refill depends on the drug reservoir volume (20 or 40 ml), drug dose, concentration and stability. The intrathecal pump must be refilled using an aseptic technique, as it is contiguous with the intrathecal space. Telemetry is used to check the pump model, reservoir size, and to adjust settings and determine refill date. A patient-controlled device that allows for self-administered boluses may improve quality of life in these patients [61]. A
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Vertebroplasty & kyphoplasty
Vertebroplasty and kyphoplasty are interventional procedures that have been developed to manage pain from vertebral collapse that results from osteoporosis or malignant disease. The technique of vertebroplasty, which involves the transpedicular delivery of polymethylmethacrylate, was initially developed for the treatment of spinal hemangiomas. The objective is primarily to provide pain relief, although the procedures also have the perpetrated benefit of vertebral stability by inhibiting the progression of fracture and further vertebral body collapse [62]. In determining appropriate candidates for vertebroplasty or kyphoplasty, physical examination and diagnostic imaging, including bone scan and MRI or CT scan, should be used to rule out other causes of back pain (i.e., facet disease or nerve compression). The patient’s pain symptoms should correspond to the level of vertebral fracture. Bone scans are helpful in determining the age of fracture, with more recent fractures corresponding to more effective pain relief from the procedure [62,63]. MRI is also used to determine age of fracture and evaluate any additional pathology that may contribute to pain. Front view
B
Back view
TENS
B
B Right
B Left
Left
Right
Figure 7. Neuromodulation techniques for treating cancer-related pain syndromes. (A) Patient with history of testicular cancer with neuropathic pain of the left testis and groin. A 16-lead spinal cord stimulator was placed in the epidural space to stimulate the dorsal columns at T6 with thoracic nerve roots stimulated at T10. (B) Diagram showing placement of TENS unit pads for patient with sacral sarcoma. Patient was able to use TENS unit to increase his ability to ambulate as part of goal-directed therapy. B: External and internal pain; TENS: Transcutaneous electric nerve stimulation.
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MANAGEMENT PERSPECTIVE Gulati, Joshi & Baqai Fractures with a greater than 80% loss of vertebral body height do not respond well to vertebroplasty and kyphoplasty [62], although there are limited series of patients with severe fractures that have shown improvement [64]. Contraindications include retropulsed bone fragment, involvement of malignancy in the epidural space, poorly localized pain, infection and patients’ inability to lay prone [62]. In addition to damage to neural and vascular structures when accessing the vertebral body, adverse effects of vertebroplasty and kyphoplasty include extravasation of cement, which may cause pressure on spinal cord and nerve roots, cement embolization and pulmonary embolization. Infection is a rare, but serious, complication. Two highly publicized randomized studies published in 2009 evaluated the use of vertebroplasty for painful osteoporotic vertebral fractures. Both studies failed to show reduced pain over the control [65,66]. There is limited evidence to suggest benefit from vertebroplasty and kyphoplasty in patients with vertebral body fractures secondary to malignancy. There are two prospective uncontrolled trials showing pain relief from vertebroplasty and kyphoplasty in patients with pathologic vertebral body fractures secondary to malignancy [67,68]. Additionally, one randomized controlled trial shows balloon kyphoplasty to be superior to nonsurgical management for cancer-related vertebral compression fractures [69]. Conclusion Various techniques are available for interventional management of cancer pain. The current literature supports the use of interventional procedures as an adjunct to pharmacologic management for cancer-related pain symptoms. While the majority of cancer-pain patients may have their pain symptoms controlled with References
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pharmacologic treatments, modulation of the sympathetic chain, peripheral nerve targets and intrathecal space is a growing discipline in cancer-pain management. A continuum now exists in the treatment of oncologic pain such that interventions may be offered at any point of a cancer patient’s pain treatment plan. Future perspective As our treatments for cancer improve, various cancers will be viewed as a chronic disease. As such, chronic pharmacologic treatments (especially those focusing on opioid management) may be insufficient in managing pain. Further work will need to be done to understand when and how to apply interventional procedures as part of a new paradigm in managing these patients. On the horizon are ultrasound guided techniques for nerve blockade and further use of neuromodulation, such as transcutaneous electric nerve stimulation, peripheral and spinal cord stimulation. These new techniques and new technologies that are applied to chronic noncancer-pain patients will have to be evaluated for their efficacy in the cancer-pain population. Further insight and research will lead to increased use of interventional techniques as part of a continuum during and after cancer patient’s oncologic treatment. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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