Efficacy spectrum of antishivering medications: Meta-analysis of randomized controlled trials

From the Departments of Neurology (SMP, HSM, AJR), Neuroscience (SMP, HSM, AJR), Neurosurgery (HSM, AJR), and Pharmacy (KB), Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY.
Critical care medicine (Impact Factor: 6.31). 08/2012; 40(11):3070-82. DOI: 10.1097/CCM.0b013e31825b931e
Source: PubMed


: Shivering after anesthesia or in the critical care setting is frequent, can be prolonged, and has the potential for serious adverse events and worsening outcomes. Furthermore, there are conflicting published data and clinical protocols on how to best treat shivering. In this study, we aimed to critically analyze the published evidence of antishivering medications.
: We systematically reviewed, categorized, and analyzed all literature on antishivering medications published in English. Target key words and study types were determined and major scientific databases (PubMed, EMBASE, the Cochrane Controlled Trials Register, Ovid-Medline, and JAMA Evidence) and individual target journals were systematically searched up to August 1, 2011.
: Publications were categorized by the pharmacological intervention used, regardless of whether the subjects were ventilated, underwent surgery, received anesthesia, or received additional medications. Randomized, double-blinded, placebo-controlled trials investigating antishivering treatment were extracted and evaluated for clinical and statistical homogeneity and, if suitable, included in a subsequent meta-analysis using linear comparisons calculating shivering risk-reduction ratios.
: A total of 41 individual and eight combination antishivering medications were tested in 124 publications containing 208 substudies and recruiting a total of 9,668 subjects. Among those, 80 publications containing 119 substudies were identified as randomized, double-blinded, placebo-controlled of which 94 substudies were subjected to linear comparison analysis.
: Study drug frequencies, calculated pooled risk benefits, and pooled numbers needed to treat of the five most frequently studied and efficacious medications were clonidine (22 studies; risk ratio: 1.6, numbers needed to treat: 4), meperidine (16; 2.2, 2), tramadol (8; 2.2, 2), nefopam (7; 2.1, 2), and ketamine (7; 1.8, 3).
: There is significant heterogeneity in the literature with respect to study methods and efficacy testing of antishivering treatments. Clonidine, meperidine, tramadol, nefopam, and ketamine were the most frequently reported pharmacological interventions and showed a variable degree of efficacy in randomized, double-blinded, placebo-controlled trials.

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    • "Ketamine has characteristics such as induction of amnesia, cerebral vasodilatation, and ICP increase, marked and transient increase in blood pressure by stimulating sympathetic system, bronchial smooth muscle relaxation, analgesia and hallucination. Ketamine, which is a competitive NMDA receptor antagonist, has been shown to inhibit postoperative shivering in some reports and studies (11-13). Ketamine induction dose is 1-2 mg/kg as IV or 4-6 mg/kg IM. "
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    ABSTRACT: One of the unpleasant side effects of general anesthesia is shivering in the process of recovery. It is an involuntary oscillatory mechanical movement that can be classified as clonic movements. These movements can affect one or several groups of skeletal muscles beginning from 5 to 30 minutes after the discontinuation of anesthesia. We aimed to study ketamine's effect on shivering after operation compared to pethidine as a way for treatment of postoperative shivering. In this study, 60 patients who underwent ENT surgery with general anesthesia and had shivering during recovery were randomly divided into two groups of 30 patients each receiving ketamine (0.2 mg/kg IV) and pethidine (0.5 mg/kg). There was no statistically significant difference between the shivering intensity in both groups. Only regarding the shivering in the first minute after entering the recovery room, there was an obvious difference between ketamine and pethidine groups which was again not statistically significant (P = 0.07). The results of this study showed that ketamine and pethidine are both equally effective in the reduction of postoperative shivering.
    Full-text · Article · May 2014 · Anesthesiology and Pain Medicine
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    • "Its effect on shivering, defined as the body's physiologic response to cold exposure and preserve heat by peripheral vasoconstriction, has been compared with various drugs, such as meperidine, tramadol, clonidine, and ketamine. Clinically, shivering is noticeable as involuntary and uncoordinated skeletal muscle contractions that increase metabolic activity generating heat and elevating the core body temperature [17]. "
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    ABSTRACT: Nefopam (NFP) is a non-opioid, non-steroidal, centrally acting analgesic drug that is derivative of the non-sedative benzoxazocine, developed and known in 1960s as fenazocine. Although the mechanisms of analgesic action of NFP are not well understood, they are similar to those of triple neurotransmitter (serotonin, norepinephrine, and dopamine) reuptake inhibitors and anticonvulsants. It has been used mainly as an analgesic drug for nociceptive pain, as well as a treatment for the prevention of postoperative shivering and hiccups. Based on NFP's mechanisms of analgesic action, it is more suitable for the treatment of neuropathic pain. Intravenous administration of NFP should be given in single doses of 20 mg slowly over 15-20 min or with continuous infusion of 60-120 mg/d to minimize adverse effects, such as nausea, cold sweating, dizziness, tachycardia, or drowsiness. The usual dose of oral administration is three to six times per day totaling 90-180 mg. The ceiling effect of its analgesia is uncertain depending on the mechanism of pain relief. In conclusion, the recently discovered dual analgesic mechanisms of action, namely, a) descending pain modulation by triple neurotransmitter reuptake inhibition similar to antidepressants, and b) inhibition of long-term potentiation mediated by NMDA from the inhibition of calcium influx like gabapentinoid anticonvulsants or blockade of voltage-sensitive sodium channels like carbamazepine, enable NFP to be used as a therapeutic agent to treat neuropathic pain.
    Full-text · Article · Apr 2014 · The Korean journal of pain

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