In patients with chronic cancer pain, combination spinal chemotherapy is often used in clinical conditions in which the response to systemic analgesia is poor (1). Small-dose intraspinal local anesthetics, when added to either epidural or intrathecal opioids, synergistically enhance the antinociceptive effects of the opioid dose, as demonstrated by isobolographic analysis (2), likely because of inhibition of neuronal excitability. Thus, the combination of intrathecally administered morphine and bupivacaine has been proposed as a fourth step of the World Health Organization analgesic ladder. Moreover, temporary use of a local anesthetic alone can allow a “drug holiday” when opioid tolerance becomes a limiting factor for treatment. The development of tolerance to morphine is delayed, and the quality of analgesia can be improved because of the morphine-sparing effect of local anesthetics (3).
Local anesthetics reduce impulse transmission by interfering with the mechanism of normal depolarization, binding to specific receptors located at the nerve membrane—more specifically, on the voltage-gated, tetrodoxin-sensitive sodium channel—and resulting in decreased or eliminated permeability to sodium ions, leading to interruption of nerve conduction. However, repetitive administration can induce the phenomenon of tachyphylaxis (4). Tachyphylaxis to local anesthetics is defined as a decrease in duration, segmental spread, or intensity of analgesia despite repeated constant dosages. Although tachyphylaxis to local anesthetics has been reported for more than two decades, the molecular mechanisms remain unknown. Different pharmacokinetic factors have been proposed to explain tachyphylaxis, including local edema, increased epidural protein concentration, changes in local anesthetic distribution in the epidural space, or a decrease of perineural pH, limiting the diffusion of the local anesthetics from the epidural space to their binding sites at the sodium channel; increased epidural blood flow; or increased local metabolism, favoring clearance of local anesthetics from the epidural space (5,6). However, reduction of local anesthetic activity has also been reported with the intrathecal route, and tachyphylaxis to local anesthetics does not result from reduced drug effectiveness at the nerve itself (7,8). Moreover, other factors of pharmacodynamic origin have been implicated, such as antagonistic effects of nucleotides or increased sodium concentration, increased afferent input from nociceptors, or receptor downregulation of the sodium channels, and often the interpretation is quite difficult because of time-dependent variations in pain or circadian changes in the duration of local anesthetic action: phenomena that are named pseudotachyphylaxis(5). The recent observation that N-methyl-d-aspartic acid (NMDA) antagonists and nitric oxide (NO) synthase inhibitors prevent the development of tachyphylaxis suggests involvement of the NO pathway in the development of tachyphylaxis (9–11). Thus tachyphylaxis, like hyperalgesia, is mediated at least in part by a spinal site of action (9).
Similarly, opioid switching often restores analgesia in patients previously not responsive to a previous opioid (12), often presenting increased nociception, opioid-induced tolerance, or hyperalgesia, which probably share common mechanisms (13). We report the experience of four patients in whom local anesthetic responsiveness was restored by changing the local anesthetic in a manner resembling opioid switching.
A 47-yr-old woman with cervical cancer locally advanced and metastasized to the lung, mediastinum, and bones was admitted to the Pain Relief and Palliative Care Unit for severe lumbar and inguinal pain, which was aggravated by movement and caused by lumbar metastases. She had received different courses of chemotherapy and radiotherapy and was receiving a morphine slow-release preparation 180 mg daily, without reporting analgesic benefit. Opioid doses were increased up to 300 mg, but escalation was stopped because of the occurrence of drowsiness and vomiting. An intrathecal catheter was placed at the L3-4 level and was connected to a subcutaneous port and then to an external pump. A morphine/bupivacaine combination was given. The combination of the drugs was balanced to obtain the best analgesic effect with minimal neurological impairment in the lower limbs. The patient obtained adequate pain relief with doses of 8 mg of morphine and 40 mg of bupivacaine daily. Concentrations were adjusted to give an infusion rate of 2–3 mL/h. Vomiting was controlled by small doses of dehydrobenzoperidol (0.9 mg/d). One month later, the patient was readmitted for uncontrolled pain. Doses of bupivacaine up to 50 mg/d were ineffective. Lidocaine 400 mg daily was combined with morphine at the same doses, and adequate analgesia was achieved. No adverse effects were reported apart from weakness of the legs. However, a computed tomography scan confirmed the neurological involvement of spinal roots by tumor. She was discharged home on Day 15.
A 43-yr-old man was admitted to the Pain Relief and Palliative Care Unit for severe abdominal pain. He had undergone a partial gastrectomy and gastrojejunum anastomosis for gastric cancer and a plexus celiac block for his pain, and he had received several courses of chemotherapy with progression of disease. He had percutaneous biliary drainage and an IV port. Recently he had presented with different episodes of gastrointestinal hemorrhage requiring blood transfusion. At admission, he was receiving a peridural infusion of morphine 15 mg, levobupivacaine 42 mg, and clonidine 0.075 mg daily, but pain was uncontrolled (10 on a numerical scale of 0–10), and he was seriously distressed. An intrathecal catheter was placed at the T10 level, tunneled, and connected to a subcutaneous port. An infusion of a combination of morphine and bupivacaine was started, and the concentration was changed to give an infusion rate of 2–3 mL/h. Doses of both drugs were escalated, aiming at balancing the mixture to achieve the best effect. Because of the appearance of somnolence, doses of morphine were maintained at 50 mg, and bupivacaine was increased up to 50 mg, daily with a progressive decrease of effect. Bupivacaine was substituted for lidocaine 500 mg daily. Pain control was optimal, and the patient was discharged after 10 days.
A 53-yr-old woman with uterine endometrial cancer was admitted to the Pain Relief and Palliative Care Unit for severe back pain radiating to the right leg; the pain was due to lumbar metastases and cancer involvement along the ileo-psoas muscle with compression of the lumbosacral plexus. She had undergone hysterectomy/ovariectomy and received radiotherapy and different courses of chemotherapy. At time of admission, she was receiving 85 mg daily of methadone without analgesic benefit. After failure of an IV titration with morphine, an intrathecal catheter at the L2-3 level connected to a subcutaneous port was positioned, and a titration of a mixture of morphine and bupivacaine was started at an infusion rate of 2–3 mL/h. Concentrations were changed according to clinical need by increasing one of the two drugs. A fentanyl patch (75 μg/d) was added to the intrathecal treatment. However, combining 40 mg of morphine and 50 mg of bupivacaine daily was effective for only a few days. Bupivacaine was substituted with lidocaine 240 mg daily. This change allowed the achievement of appropriate analgesia. The patient was discharged home on Day 19.
A 55-yr-old patient with small-cell lung carcinoma, presenting pleural involvement unresponsive to chemotherapy, had been previously treated for 4 mo with intrathecal infusion through a subcutaneous port at constant doses of morphine and bupivacaine (10 mg and 25 mg, respectively) for severe thoracic pain caused by wall involvement that was unresponsive to systemic opioids. The catheter tip was positioned at the T9 level. Doses of bupivacaine and morphine were rapidly escalated (ratio 1:1 at an infusion rate of 2–3 mL/d), with partial and temporary pain relief; frequent extra doses of IV morphine were required. When bupivacaine 60 mg daily was substituted for lidocaine 500 mg with morphine 50 mg daily, pain control was finally achieved. He presented with motor weakness, and doses of lidocaine were decreased to 400 mg daily. He was discharged home on Day 8.
The cases presented suggest that substitution of bupivacaine with lidocaine may allow recovery from tachyphylaxis or improve analgesia in conditions in which hyperalgesia is developing in cancer patients treated with a combination of intrathecal morphine and bupivacaine. No other causes of a progressive decrease in anesthetic effect could be detected. In Patient 3, the analgesic benefit of bupivacaine was very short, and the decrease in analgesia developed in a few days. Switching from bupivacaine to lidocaine, however, provided useful analgesia while maintaining the same dose of morphine. This observation has important clinical implications; this method provides further analgesia in patients with a poor response to intrathecal treatment and resembles, in some ways, the outcome reported with opioid switching in critical situations of poor opioid response. The real mechanism of the development of tachyphylaxis is poorly understood. Repeated injections of a constant dose of local anesthetic result in a marked decrease in the duration of the blocks. Studies have shown that tachyphylaxis, like hyperalgesia, is mediated in part by a spinal site of action (9).
In animal models, hyperalgesia accelerated local anesthetic tachyphylaxis, and the noncompetitive NMDA receptor antagonist MK-801 prevented both hyperalgesia and tachyphylaxis. NO is thought to be a second messenger for NMDA pathways in the spinal cord and appears to be involved in spinal mechanisms of hyperalgesia (10,11). The observation that NMDA antagonists and NO synthase inhibitors prevent the development of tachyphylaxis suggests involvement of the NO pathway in the development of tachyphylaxis. Accordingly, NMDA antagonists or NO synthase inhibitors may prevent tachyphylaxis (5). Many subtypes of sodium channel are differentially expressed in sensory neurons in the presence of continuous and high-intensity discharges from nerve or tissue injury. It has been observed that, because lidocaine seems to be most effective at blocking sodium channels in a frequency-dependent manner (15), constant nerve depolarization increases the potency of lidocaine block (14) and could preferentially block certain subtypes of sodium channels (16) involved in injury-induced pathologic depolarization without affecting the sodium channels involved in normal signaling (17). Lidocaine has also been reported to inhibit reverse hyperalgesia and glutamate-mediated excitation in the spinal dorsal horn (17,18). This observation can also lend support to the possible differences observed between local anesthetics on the slope or shape of the dose-response curve. Moreover, lidocaine has been found to reduce the discharge of pain-facilitation cells from retroventral medulla to spinal neurons through the dorsolateral funiculus (19).
Although there is no clear explanation for the phenomenon of tachyphylaxis, patients who are not responsive to intrathecal therapy with morphine and bupivacaine switched to another local anesthetic, like lidocaine, may have an improved analgesia. This dynamic treatment may either attenuate the response to nociceptive input or interfere with the neuronal plasticity evoked by such input, producing a sort of spinal amnesia (20,21). Larger studies are needed to confirm these preliminary observations. It should be remembered, however, that lidocaine appears to have a higher neurotoxic potential than bupivacaine, when given intrathecally (22).
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