[Painful hyperexcitability syndrome with oxaliplatin containing chemotherapy. Clinical features, pathophysiology and therapeutic options].
Neurologische Klinik, Knappschaftskrankenhaus Bochum-Langendreer, Ruhr-Universität Bochum, In der Schornau 23-25, 44892, Bochum, Deutschland. Der Schmerz
(Impact Factor: 1.02).
The platinum derivative oxaliplatin is widely used in colorectal cancer. Its side effects differ from those of the other platinum compounds cisplatin and carboplatin. An acute, painful hyperexcitability syndrome (HES) accompanied by cold induced paresthesia, dysesthesia and myotonia is unique to oxaliplatin, whereas a chronic, peripheral sensory neuropathy (PSN) can be caused by all platinum compounds. It is believed that HES is the result of peripheral nerve hyperexcitability as a consequence of voltage-gated sodium channel dysfunction, which may be caused by calcium level imbalance. Therapeutic options for HES are the administration of calcium and magnesium, the serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine and the thiophosphate amifostine.
Available from: Luiz Fernando Ferrari
- "Inflammatory pain was produced by focal intradermal injection of carrageenan on the dorsum of the hind paw (Guilbaud et al., 1989a; Guilbaud et al., 1989b; Dawson et al., 1991; Aley et al., 2000; Khasar et al., 2008). Three neuropathic pain models were tested; one of these was a model of alcoholic painful peripheral neuropathy (Diamond and Messing, 1994; Monforte et al., 1995; Kielhorn, 1996; Ortiz-Plata et al., 1998; Dina et al., 2000); and two models (early and late phase neuropathy) were induced by intravenous injection of the chemotherapeutic agent oxaliplatin (Joseph et al., 2008; Kowalski et al., 2008). Enhanced cytokine hyperalgesia, a model of chronic widespread pain syndromes such as fibromyalgia (Khasar et al., 2005) was induced by cytokine administration after chronic unpredictable stress. "
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ABSTRACT: Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of the endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis, we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated, noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain or the early phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits and that this effect is sympathoadrenal dependent.
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ABSTRACT: Die Behandlung des metastasierten kolorektalen Karzinoms (KRK) hat sich in den letzten Jahren entscheidend gewandelt und wird
zunehmend zur individualisierten Therapie. Seit wenigen Jahren stehen neben einer Reihe von hochwirksamen Chemotherapeutika
monoklonale Antikörper für die Behandlung zur Verfügung. Mittlerweile hängt die Entscheidung über die Art und Dauer der Therapie
stark davon ab, welches Ausmaß die Erkrankung hat und ob der Patient symptomatisch ist. Auch das Vorliegen bestimmter genetischer
Veränderungen beeinflusst die Wahl der Substanz. Therapieziel in der palliativen Situation bleibt die Verlängerung des Überlebens
und eine Verbesserung der Lebensqualität. Bei der Patientengruppe, die primär nicht resektable Lebermetastasen aufweist, die
durch Verkleinerung resezierbar werden können, kann durch eine intensive neoadjuvante Therapie sekundär die Möglichkeit der
chirurgischen Entfernung der Tumormanifestationen herbeigeführt und die Patienten können so potenziell geheilt werden.
Treatment of advanced colorectal carcinoma (aCRC) has changed considerably over the past few years and is becoming increasingly
individualized. In addition to highly effective chemotherapeutics, monoclonal antibodies became available for treating CRC
a few years ago. The decision as to the type and duration of treatment now heavily depends on the extent of the disease and
whether the patient is symptomatic. The existence of certain genetic changes also affects the choice of substance. The aim
of palliative treatment remains to extend the patient’s life and to improve quality of life. In a patient group with primarily
non-resectable liver metastases that may become resectable following a reduction in size, intensive neoadjuvant therapy can
create the option of secondary surgical removal of the tumor manifestations and thus potentially cure the patients.
Available from: Oliver Bogen
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ABSTRACT: The toxicity profile of oxaliplatin, a platinum derivative currently used in the treatment of colorectal cancer, differs from those of the other platinum compounds, cisplatin and carboplatin. Oxaliplatin treatment induces an acute neurotoxicity characterized by a rapid onset of cold-induced distal dysesthesia and a chronic sensory peripheral neuropathy. A single intravenous dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia and heat and cold allodynia; repeated administration intensified symptoms. A single intradermal dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia. A single dose intravenous oxaliplatin also lowered thresholds and increased responses of C-fiber nociceptors to mechanical stimulation, confirming a peripheral site of action. Whereas peripheral administration of inhibitors of second messengers implicated in models of other painful peripheral neuropathies (PKA, PKC, NO, Ca(2+), and caspase) had no effect; both systemic and local administration of antioxidants (acetyl-L-carnitine, alpha-lipoic acid or vitamin C), all markedly inhibited oxaliplatin-induced hyperalgesia. Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia. We suggest that oxaliplatin acts on IB4 (+)-nociceptors to induce oxidative stress-dependent acute peripheral sensory neuropathy. PERSPECTIVE: Many drugs used to treat cancer produce pain as their dose-limiting side effect. We used a model of this pain syndrome induced by oxaliplatin to demonstrate that pain is produced by action on a subset of nociceptors, the IB4-positive DRG neurons. This information could help define cellular targets against which protective therapies could be developed.
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