Advances in the therapy of cancer pain: from novel experimental models to evidence-based treatments

Cancer related pain may be due to the malignant disease itself, or subsequent to treatments, such as surgery, chemotherapy or radiation therapy. The pathophysiology of pain due to cancer may be complex and include a variety of nociceptive, inflammatory, and neuropathic mechanisms. Despite modern advances in pharmacotherapy, cancer pain remains overall under-treated in a world-wide scale, and a main reason is lack of understanding of its pertinent pathophysiology and basic pharmacology. Recently, pertinent animal models have facilitated understanding of the pathobiology and have advanced the pharmacology of cancer pain, with significant translational applicability to clinical practice. Furthermore, quantitative and qualitative systematic reviews, integrating the best available evidence, indicate the validity of treatments that fit into an expanded view of the WHO-analgesic ladder. Appropriate current treatments include a valid therapeutic role of non-opioid and opioid analgesics, adjuvants -such as gabapentin, biphosphonates, palliative radiation therapy and radiopharmaceutical compounds, and interventional pain therapy (including neuraxial drug infusion and verterbroplasty for spine metastases) in selected patients. Overall, experimental animal models simulating cancer pain have been useful in providing pertinent information on the pathophysiology of cancer pain, and provide a testing ground for established and novel therapies, which are validated by clinical evidence. This is clinically significant, considering the epidemiological dimensions and the problematic nature of cancer pain

Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation

<p>Abstract</p> <p>Background</p> <p>ATP-sensitive potassium (K_ATP) channels in neurons regulate excitability, neurotransmitter release and mediate protection from cell-death. Furthermore, activation of K_ATPchannels is suppressed in DRG neurons after painful-like nerve injury. NO-dependent mechanisms modulate both K_ATPchannels and participate in the pathophysiology and pharmacology of neuropathic pain. Therefore, we investigated NO modulation of K_ATPchannels in control and axotomized DRG neurons.</p> <p>Results</p> <p>Cell-attached and cell-free recordings of K_ATPcurrents in large DRG neurons from control rats (sham surgery, SS) revealed activation of K_ATPchannels by NO exogenously released by the NO donor SNAP, through decreased sensitivity to [ATP]i.</p> <p>This NO-induced K_ATPchannel activation was not altered in ganglia from animals that demonstrated sustained hyperalgesia-type response to nociceptive stimulation following spinal nerve ligation. However, baseline opening of K_ATPchannels and their activation induced by metabolic inhibition was suppressed by axotomy. Failure to block the NO-mediated amplification of K_ATPcurrents with specific inhibitors of sGC and PKG indicated that the classical sGC/cGMP/PKG signaling pathway was not involved in the activation by SNAP. NO-induced activation of K_ATPchannels remained intact in cell-free patches, was reversed by DTT, a thiol-reducing agent, and prevented by NEM, a thiol-alkylating agent. Other findings indicated that the mechanisms by which NO activates K_ATPchannels involve direct S-nitrosylation of cysteine residues in the SUR1 subunit. Specifically, current through recombinant wild-type SUR1/Kir6.2 channels expressed in COS7 cells was activated by NO, but channels formed only from truncated isoform Kir6.2 subunits without SUR1 subunits were insensitive to NO. Further, mutagenesis of SUR1 indicated that NO-induced K_ATPchannel activation involves interaction of NO with residues in the NBD1 of the SUR1 subunit.</p> <p>Conclusion</p> <p>NO activates K_ATPchannels in large DRG neurons via direct S-nitrosylation of cysteine residues in the SUR1 subunit. The capacity of NO to activate K_ATPchannels via this mechanism remains intact even after spinal nerve ligation, thus providing opportunities for selective pharmacological enhancement of K_ATPcurrent even after decrease of this current by painful-like nerve injury.</p

Systemic Opioids Enhance the Spread of Sensory Analgesia Produced by Intrathecal Lidocaine

The effect of different doses of fentanyl and nalbuphine on the spread of spinal analgesia produced by lidocaine was studied in 68 patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia. Patients were randomly assigned to six groupsfentanyl A, B, or C (FA, FB, FC) or nalbuphine A, B, or C (NA, NB, NC), which received intravenous (IV) 50, 100, or 150 μg of fentanyl or 10, 15, or 20 mg of nalbuphine, respectively, 20 min after spinal anesthesia with lidocaine. We tested the level of spinal analgesia with pinprick sensation 20 min after spinal anesthesia and 10 min after the opioid administration, when 0.4 mg of naloxone was administered IV. The levels of sensory analgesia were reassessed 10 min after naloxone. Ten minutes after fentanyl or nalbuphine, the level of analgesia increased (1.8 ± 1.7, 3.1 ± 1.2, and 4.1 ± 1.5 cm, in the FA, FB, and FC groups and 1.9 ± 0.9, 2.6 ± 1.4, and 3.7 ± 2.2 cm in the NA, NB, and NC groups, respectively). The increases in the level of analgesia differed significantly between the fentanyl groups (F = 8.0939; df = 2,35; P < 0.001), the increase produced by 150 μg being significantly higher than produced by 50 μg of fentanyl (limits of confidence −4.236809 and −0.4431909; P < 0.01). Naloxone reversed the effect of fentanyl and 10 min after its administration the fentanyl groups did not differ with regard to the level of spinal analgesia. Nalbuphine also enhanced the spread of sensory analgesia produced by lidocaine, but the nalbuphine groups did not differ significantly between them with regard to the level of analgesia 10 min after its administration as well 10 min after naloxone treatment. Naloxone completely antagonized the effect of fentanyl on spinal analgesia but only partially the effect of nalbuphine. Fentanyl 100 and 150 μg significantly increased the level of analgesia when compared with equipotent doses of nalbuphine 10 and 15 mg (P < 0.02 and P < 0.05, respectively). We conclude that systemic fentanyl and nalbuphine enhance the spread of spinal analgesia in a dose-dependent manner. This effect is antagonized by naloxone, and may be clinically important when a spinal block dissipates before completion of surgery