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This randomised, multicentre, double-blind, three-arm, placebo-controlled trial compared a topical combination of 35% comfrey root extract plus 1.2% methyl nicotinate versus a single preparation of methyl nicotinate or placebo cream for relief of acute upper or low back pain. 379 patients were randomly assigned to three groups (combination, n = 163; methyl nicotinate, n = 164; placebo, n = 52). They applied a 12 cm layer of cream three times daily for 5 days. The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. Secondary measures included back pain at rest, pressure algometry, consumption of analgesic medication, functional impairment measured with Oswestry Disability Index, and global assessment of response. The AUC of the VAS on active standardised movement was markedly smaller in the combination treatment group than in the methyl nicotinate and in the placebo group (ANOVA: p < 0.0001). The combination demonstrated superiority to the two other treatment arms, while methyl nicotinate displayed a considerable effect as well. Copyright © 2012 John Wiley & Sons, Ltd.
Acute back pain of the upper or low back is a widespread condition that impairs quality of life and functional movement in a large number of people (McCarberg, 2010; Balagué et al., 2012). However, patients seek for pain relief and treat their pain symptoms often in self-medication. There are many potential causes for acute back pain, and precise causation is difficult to determine. As a consequence, the treatment of acute back pain is a complex issue. Recommended topical and systemic pharmacologic treatments for acute low back pain include application of superficial heat, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants/benzodiazepines, and opioids including tramadol (McCarberg, 2010).
The topical pharmacotherapeutic approach has generally included hyperaemising topical drugs such as nicotinates with the intention to soften and relax the contracted muscle area, thereby indirectly alleviating the pain caused by this contraction. In addition to heat or hyperaemia, the treatment strategy has recently been augmented by a direct anti-inflammatory topical approach – for instance with diclofenac.
Topical treatments with anti-inflammatory and analgesic properties provide an interesting alternative, taking into account the potential adverse effects of oral therapies (e.g. gastrointestinal and renal side effects of NSAIDs and analgesics). Extracts of comfrey in mono preparations and in combination with methyl nicotinate have a long tradition of use as topical treatment (Englert et al., 2005; Staiger, 2005; Staiger, 2007; European Scientific Cooperative on Phytotherapy (ESCOP), 2009; Staiger, 2012) In clinical studies, the antiphlogistic properties of comfrey extract could be demonstrated in various indications (Petersen et al., 1993; Koll et al., 2004; Predel et al., 2005; D'Anchise et al., 2007; Grube et al., 2007; Giannetti et al., 2010).
The efficacy of comfrey root extract ointment was evaluated in a randomised, double-blind, placebo-controlled multicentre study involving 142 patients with a unilateral ankle sprain. Compared to placebo, the superiority of the verum treatment was significant (Koll et al., 2004). The same ointment was compared with a gel preparation containing 1% of diclofenac in a randomised, single-blind multicentre study involving patients with the same condition. The results showed that the comfrey ointment was not inferior to diclofenac gel (Predel et al., 2005). In some variables there was even evidence of superiority of the comfrey ointment (D'Anchise et al., 2007).
Another randomised, double-blind, placebo-controlled clinical trial investigated the effect of the same ointment over a 3-week period in 220 patients with painful osteoarthritis of the knee. The superiority (p < 0.001) of the verum group over the placebo group was confirmed. Pain was reduced, mobility of the knee improved, and quality of life increased (Grube et al., 2007).
The effect of two concentrations of topical, comfrey-based botanical creams containing a blend of tannic acid and eucalyptus was compared to a eucalyptus reference cream in patients with primary osteoarthritis of the knee. Both active topical comfrey formulations were effective in relieving pain and stiffness and in improving physical functioning and were superior to placebo (Smith and Jacobson, 2011).
In the treatment of acute upper or low back pain, a study was conducted as a double-blind, multicentre, randomised clinical trial with parallel group design over a period of 5 days (Giannetti et al., 2010). One-hundred and twenty patients with acute upper or lower back pain were treated three times a day, 4 g per application. They used either a verum cream containing comfrey root fluid extract (1:2, 35.0 g, extraction solvent ethanol 60% (v/v), less than 0.35 ppm of pyrrolizidine alkaloids, Kytta-Salbe® f) or a corresponding placebo. The trial included four visits and was performed at the German Sport University in Cologne (Deutsche Sporthochschule) and three additional ambulatory centres for orthopaedics and sports medicine. The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. The pain intensity on VAS was assessed at performance of standardised, muscle group specific tests. The secondary objectives were back pain at rest using assessment by patient on VAS, pressure algometry (pain–time curve; AUC over 5 days), global assessment of efficacy by the patient and the investigator, intake of analgesic medication, and functional impairment measured with the Oswestry Disability Index.
The results were clear-cut and consistent across all primary and secondary efficacy variables. Comfrey root extract showed a remarkably potent, fast-acting, and clinically relevant effect in reducing acute back pain. The pain intensity on active standardised movement decreased on average (median) approximately 95.2% in the comfrey extract group (104.8–12.7 mm; mean VAS sum) and 37.8% in the placebo group (100.0–56.5 mm; mean VAS sum) (p < 0,001). Compared with placebo, superiority of the verum treatment was significant with regard to secondary efficacy variables (each p < 0.001). Both the AUC of the reported back pain at rest, the AUC of the pressure algometry in the trigger point, as well as the global assessment of the efficacy by the patients and the investigators showed a clinically relevant effect in reducing acute back pain. For the first time, a fast-acting effect of the ointment (1 h) was also observed. After 1 h, the pain intensity had already decreased about 33.0% in the comfrey group (104.8 to 60.4 mm; mean VAS sum) and 12.0% in the placebo group (100.00 to 86.5; mean VAS sum) indicating an early onset of the treatment effect.
Besides creams with the single comfrey root extract, a combination with methyl nicotinate has been used for decades. A non-published pilot study showed a favourable effect of the combination in patients with lumbar spine syndrome. Furthermore, the antiphlogistic and analgetic properties of the drug were evaluated in a post-marketing surveillance study. A total of 167 patients who used the preparation externally for contusions and distortions, muscle and joint pain were documented. The key symptoms were clearly reduced (Klingenburg, 2004).
It is therefore justified and reasonable to assume a beneficial effect of the combination of comfrey root extract and methyl nicotinate also in patients suffering from acute back pain such as upper or low back pain and to conduct a GCP-compliant clinical trial to document this assumed efficacy. For acute back pain, the Note for Guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain requires a study period of less than 1 week (Committee for Proprietary Medicinal Products, 2002).
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The results demonstrate that the topical combination of comfrey root extract and methyl nicotinate has a clinically relevant, favourable impact on the outcomes of patients suffering from acute upper or low back pain. Patients treated with the combination had statistically significant and clinically relevant reductions in pain scores and increases in tenderness. Significantly more patients in the combination group reached a virtually pain-free status at visit 4 compared to the placebo group as well as compared to the methyl nicotinate group, as documented by the results of the global assessment of efficacy by the patients and by the investigators. They reached a pain-free condition significantly earlier than patients in the methyl nicotinate and those in the placebo group.
Further, the clinical trial showed that methyl nicotinate contributes substantially to the efficacy of the combination product, reducing the primary parameter by 31% compared to placebo.
Patients using topical drugs for self-medication do not usually know the precise cause of their pain; however they do seek pain relief. This trial might have limitations as we did not include, for example, a pain diary, which may have allowed further, relevant, detailed data analysis. However, the efficacy demonstrated reflects the pharmaceutical treatment routine of this patient group to quite an extent.