DÄ internationalArchive50/2014Drug Treatments for Pruritus in Adult Palliative Care

Original article

Drug Treatments for Pruritus in Adult Palliative Care

Dtsch Arztebl Int 2014; 111(50): 863-70; DOI: 10.3238/arztebl.2014.0863

Siemens, W; Xander, C; Meerpohl, J J; Antes, G; Becker, G

Background: Pruritus is a rare but troublesome symptom in palliative-care patients with a variety of underlying diseases. The pharmacotherapy of pruritus is often off-label, and an evidence-based evaluation is needed.

Method: A Cochrane Review published in 2013 was updated with a systematic literature search up to January 2014. Randomized and controlled trials (RCTs) with adult palliative-care patients were included.

Results: In the 43 RCTs that were analyzed, three of which were more recent than the Cochrane Review, 8 clinically relevant active substances were investigated in a total of 19 RCTs. Effective drugs for pruritus in palliative-care patients included paroxetine for pruritus of diverse origins (1 RCT; strong effect) and indomethacin for HIV-induced prutitus (1 RCT; median effect = moderate reduction). Effective drugs for pruritus in uremia were gabapentin (2 RCTs; strong effect), nalfurafin (3 RCTs; moderate effect), naltrexone (3 RCTs; heterogeneous effects, ranging from weak to strong), and cromoglicic acid (2 RCTs; moderate to strong effect). Effective drugs for cholestatic pruritus were rifampicin (3 RCTs; moderate effect), flumecinol (2 RCTs; weak to moderate effect), and naltrexone (2 RCTs; moderate to strong effect). Undesired effects were most common with naltrexone (dizziness: 0%–50%, nausea: 0%–50%) and nalfurafin (nasopharyngitis: 8%–12%, insomnia: 7%–15%).

Conclusion: In view of the diverse etiologies of pruritus in palliative-care patients, careful consideration should be given to the choice of drug used to treat it. The substances listed here have moderate to strong antipruritic effects and merit further study in RCTs of high methodological quality.

LNSLNS

Pruritus is defined as an unpleasant sensation that triggers the need for a mechanical response, such as scratching, rubbing, or pressure (1). Pruritus is not a disease entity but—similar to pain—a symptom that is only captured by means of the individual patient’s subjective perception (24) with biopsychosocial triggers and amplifiers, which is based on complex pathomechanisms that have not been conclusively researched (57). In palliative care patients, pruritus is a distinctive feature, owing to its multifactorial nature. Typically it occurs as an accompanying symptom in several underlying disorders (89),

  • as cholestatic pruritus in disorders of the liver or biliary duct
  • as uremic pruritus in chronic renal disorders (10)
  • as paraneoplastic pruritus in the context of a malignancy
  • as HIV associated pruritus and
  • as medication induced pruritus (10).

In this context, the prevalence of pruritus varies between 1% after administration of opioids (11) and 25–85% in patients with renal failure (10).

As no gold standard exists for the treatment of pruritus in patients with advanced life-threatening disorders, this systematic review aims to explain and assess the effectiveness of pharmacological interventions. We intentionally did not include pruritus as the symptom of a primary skin disorder.

Method

On the basis of the search strategy of a Cochrane review published in 2013 (12), we conducted an electronic database search for the time period from January 2012 to January 2014. We exclusively included and evaluated randomized controlled (which implies comparisons of medications) trials (RCTs) of pharmacological interventions in which pruritus was the primary end point. Patients aged 18 or older who had pruritus in combination with an incurable advanced malignant or non-malignant disorder were considered to be palliative care patients (12). Further methodological information can be found in Xander et al. (12).

In order to identify relevant studies we searched the databases MEDLINE via Ovid, the Cochrane Library via Wiley, EMBASE via DIMDI, BIOSIS via Web of Science, CINAHL via EBSCO, and PsycINFO via EBSCO (15 January 2014). Two of the authors (Xander, Siemens) reviewed the studies’ titles and abstracts independently from each other. The selected studies were extracted according to a predefined form (Siemens). The extraction table and the full text were collated by one of the two authors (Xander), and inconsistencies were resolved by a third author (Becker).

Furthermore, clinically relevant substances from the Cochrane review (12) were selected and described and evaluated in this review article. Wherever possible, we calculated the mean difference and Cohen’s d between the placebo and intervention groups when these were not reported in the study (13, 14).

Results

In addition to the 40 identified studies in the Cochrane review by Xander et al. (12), our updated search identified three additional studies that were included (Figure, Table 1). The eTable summarizes the results of eight effective and clinically relevant substances from 19 RCTs (see [12] and updated search). Because of our study’s limited scope, only clinically relevant substances were included. The Cochrane review by Xander et al. (12) provides a complete overview.

Selection of analyzed studies
Selection of analyzed studies
Figure
Selection of analyzed studies
Substances for uremic pruritus: randomized, controlled studies from updated search
Substances for uremic pruritus: randomized, controlled studies from updated search
Table 1
Substances for uremic pruritus: randomized, controlled studies from updated search

Ondansetron and colesevelam tend to be ineffective against pruritus. According to the results of one RCT each per substance—with small case numbers (8–29 patients per group)—the following substances are potentially effective: activated charcoal (oral), colestyramine, sertraline, doxepin, thalidomide, montelukast, erythropoietin, propofol, lidocaine, tacrolimus, and pramoxine hydrochloride (12).

In a study with one week’s treatment duration, palliative care patients (n=26) with pruritus of diverse origin were investigated. In this setting, paroxetine (a serotonin reuptake inhibitor, SSRI) reduced pruritus in patients with primarily malignant underlying disorders (21/26 of participants) by up to 1.35 points on the numerical analogue scale (NAS, 0–10, 95% confidence interval [95% CI] 0.61 to 2.08; p=0.001; days [d]=3.3) within the final three days of treatment (15).

In patients with uremic pruritus, administration of the anticonvulsant gabapentin resulted in a notable reduction in pruritus in two RCTs compared with placebo, of 5.2 cm and 6.4 cm on the visual analogue scale (VAS: 0–10 cm) (16, 17).

Wikström et al. (18) combined in a meta-analysis two RCTs that tested nalfurafine—a κ-opioid receptor agonist—versus placebo. The result was a reduction in pruritus on the VAS by 7.3 mm (0–100 mm; 95% CI: 0.17 mm to 14.4 mm; p=0.0447). Kumagai et al. (19) reported a reduction in pruritus by up to 10 mm (VAS: 0–100 mm; 95% CI: 4 mm to 14 mm; p=0.0001).

For the opioid antagonist naltrexone, Peer et al. showed in a crossover study (20) a reduction in pruritus on the VAS (0–10 cm) in Group A of 9.9 cm (interquartile range 9.895–9.95 cm to 2.1 cm (IQR: 1.5–2.15 cm; p=0.001) and in Group B of 9.9 cm (IQR: 9.3–10.0 cm) to 1.0 cm (IQR: 0.4–11.15 cm; p<0.001). The difference to the placebo group from day 2 to day 7 was ≥5 cm (p<0.05). In another study (21) with lower baseline values (5.5 cm and 6.5 cm per group); VAS 0–10 cm), administration of naltrexone resulted in a statistically non-significant reduction of pruritus of 29% (95% CI: 18.7 to 39.6; p=0.095). A study by Legroux-Crespel (22) also showed a small reduction in pruritus (VAS: 0=-10 cm; naltrexone: 0.4 cm; p=0.01; loratadine: 0.89 cm; p<0.01).

In a study conducted by Feily et al. (23), topically applied cromoglicate (cromoglycate) resulted in a reduction of pruritus (VAS: 0–5) of 2.5 (standard deviation [SD]: 1.1) to 0.3 (SD: 1.3) (p<0.04; d=0.74)—one point below the value of the placebo group (1.3±1.4). In a study by Vessal et al., the pruritus value of the cromoglicate group (systemically administered) was by 4.68 points (VAS: 0–10; p<0.001; d=1.6) lower than in the placebo group (24).

In patients with cholestatic pruritus, rifampicin (an ansamycin antibiotic) lowered the pruritus on a four-step scale (04) by 66.7% from 2.4 (SD: 0.6) to 0.8 (SD: 0.9) (25). Podesta et al. (26) found for rifampicin that pruritus completely disappeared in 79% of patients and partly disappeared in 21% (p<0.001 compared with placebo). Ghent et al. noted significant differences during a 14-day treatment period, with mean differences between 24 mm and 38 mm (VAS: 0–100 mm) between the rifampicin and placebo groups on days 4, 5, 10, and 11 (27).

Flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol) was investigated in two studies at different dosages (600 mg/week and 300 mg/d) (28). The pruritus measurement in one of the studies (600 mg/week) resulted in a group difference relating to the median improvement of 8 mm on the VAS (0–100 mm; 95% CI: –2.1 mm to 20.8 mm; p=0.17) in favor of the intervention group.

In the other study (300 mg/d), a median reduction of pruritus of 4.0 mm (IQR: –22 to 10 mm) in the placebo group compared with a median reduction of 21.7 mm (IQR: 12–18 mm) in the flumecinol group (p<0.02) was reported. Using naltrexone, Wolfhagen et al. (29) reduced cholestatic pruritus (VAS: 0–100 mm) in eight patients during the day by 62% (95% CI: 32% to 92%; p=0.042) and during the night by 51% (95% CI: 20% to 82%; p=0.019) compared with placebo. Furthermore, Terg et al. (30) found for the comparison of naltrexone versus placebo (VAS: 0–10 cm) at daytime a mean difference of 1.79 cm (p=0.006; d=0.75) and at nighttime of 1.64 cm (p=0.01; d=0.66).

For patients with HIV induced pruritus, a four-arm study (hydroxyzine hydrochloride [HCl] versus pentoxifylline versus indometacin versus triamcinolone) showed a median moderate pruritus reduction as a result of the non-steroidal antirheumatic drug indometacin (median 3; scale 0–4; n=10) (31).

Our updated review included three studies (Table 1, Figure) that investigated the treatment of patients with uremic pruritus and cromoglicate (23), zinc sulfate (32), and fish oil (33). The mean reduction in pruritus was significantly greater in the zinc sulfate group (p=0.018) than in the placebo group (32). The study reported by Ghanei et al. showed a reduction in pruritus of 65% for fish oil, whereas the reduction in the placebo group was 15% (p=0.0001) (33).

Table 2 evaluates the 19 studies from the eTable with the studies from our updated search (Table 1) in accordance with the criteria of Cohen (13) and Strand et al. (34) by using combinable symbols (0/+/++). The use of the evaluation symbols is an intentional simplification that reduces information in favor of an overview. In conclusion, the eFigure shows the risk of bias of the included studies, according to the standards of the Cochrane Collaboration.

Effectiveness of substances for pruritus
Effectiveness of substances for pruritus
Table 2
Effectiveness of substances for pruritus
Clinically relevant pharmacological interventions for pruritus
Clinically relevant pharmacological interventions for pruritus
eTable
Clinically relevant pharmacological interventions for pruritus

Discussion

The present systematic review includes almost eight clinically active substances (19 RCTs) and a total of 614 patients (eTable). Furthermore, the study includes the description of three studies from our updated search (Table 1) as well as an assessment of the presented studies with regard to the effectiveness of the substances (Table 2) and the risk of bias (eFigure).

Assessment of bias risk
Assessment of bias risk
eFigure
Assessment of bias risk

Although all included studies were RCTs, they had substantial methodological differences. The calculation of effect sizes (for example, Cohen’s d, Hedges’s g) was not found in any of the studies (35). In interpreting the studies, it needs to be borne in mind that case numbers, duration of the intervention, and dosages vary.

Furthermore it should be pointed out that severe pruritus is tendentially associated with greater effects of substances (16, 17, 20, 24). In order to be able to attribute differences between groups in clinical studies to the intervention, identical baseline values of the study groups are required, among other things. Different (25, 29) or mean (16, 17, 22, 26) baseline values of the intervention and control groups may result in a slight overestimate of the results of some studies. The lacking baseline measurements (19, 27, 31) and measures of dispersion (27, 31) are not conclusive either.

Palliative care patients in general (n = 26)

Although paroxetine resulted in a mean difference of 1.35 points (95% CI: 0.61 to 2.08; p=0.002; d=3.3) after only one week’s treatment, it showed no effect at all in 5 patients (19%) (15). The quality of the evidence for the effectiveness of paroxetine will therefore have to be considered low, in view of the small sample size.

Patients with uremic pruritus (n=471)

For the substance nalfurafine, the reported results were consistent, albeit with small, and in some cases non-significant, differences in the mean values between the placebo and intervention groups (7.29–12.3 mm; VAS: 0–100 mm) (18, 19). In view of only 3 dropouts per dosage group, and in view of the large study reported by Kumagai et al. (>110 participants per group), the safety of nalfurafine can be assessed as high.

For the proof of efficacy, however, the authors reported only the changes in the VAS without explicitly naming baseline values. On considering the baseline measurements of the gabapentin studies (16, 17) the striking fact is that patients had higher entry values on the VAS (0–10 cm) than in the two studies reported by Wikström et al. (18), which somewhat relativizes the larger effect of gabapentin (5.2–6.4 cm; VAS: 0–10 cm). On the other hand, it should be noted that with the exception of Wikström et al. (18), the study duration of two weeks was not exceeded in the other nalfurafine studies and therefore a comparison with the four-week treatment duration in the gabapentin studies is possible to a limited degree only (eFigure). The effectiveness of naltrexone cannot be assessed conclusively. Although, compared with the placebo group, a notable difference was seen in severe pruritus (>9 VAS; VAS: 0–10 cm), of ≥5 cm (p<0.05) (20), this was not confirmed in two further studies (21, 22), in spite of identical medication and a longer treatment period—presumably because of the lower pruritus level at baseline. Furthermore, the naltrexone studies had many dropouts because of adverse effects (30.4–46.2%), with the exception of the study by Peer et al. (20).

Although cromoglicate was effective in both studies we identified (23, 24), the true effect is difficult to estimate because of small case numbers and differences between the studies (pruritus baseline level, duration of treatment, form of application; 34% therapy dropouts in Vessal et al.). Neither of the two studies had any dropouts because of adverse effects; consequently, systemically and topically applied cromoglicate can probably be regarded as safe.

Patients with cholestatic pruritus (n = 107)

Within the rifampicin studies, the comparability is limited because of the difference in measuring instrument. Podesta et al. present a result that could be questioned, according to which 11 out of 14 patients (79%) experience complete resolution of their pruritus (pruritus baseline level: 72 mm; SD: 19 mm; VAS: 0–100 mm) (26). On a sensible scale such as the VAS (0–100 mm) this finding does not seem plausible after only a one-week treatment course of rifampicin. A qualified proof of efficacy is given by the study reported by Ghent et al., in which corresponding days of two weeks’ treatment are compared. The fact that only days 4, 5, and 10 show significant differences compared with placebo (24 mm; 36.5 mm; 32 mm, 38 mm; VAS: 0–100 mm) implies wide dispersion (not reported) of the data and the possibility of results that reach significance by sheer chance (27). Bachs et al. point out that in one case, rifampicin led to hemolytic anemia and renal failure. The small case numbers make precise conclusions regarding the safety of rifampicin impossible (25).

For flumecinol, efficacy was seen only for a dosage of 300 mg twice daily, but not for 600 mg/week (28). Since no adverse effects or dropouts were reported, one may cautiously assume relative safety for flumecinol, in spite of the small case numbers. The limited effectiveness was partly explained by the low pruritus levels (median ≤50 mm; VAS: 0–100 mm) at baseline.

For naltrexone, two studies (29, 30) with small case numbers (n=8; n=20) exist, which show its efficacy, albeit with some limitations: the effect of naltrexone compared with placebo shows additional increases in the study by Wolfhagen et al. because the pruritus in the placebo group had increased for reasons unknown (29). Furthermore, the mean baseline level of the naltrexone group is notably higher than that of the placebo group (daytime: 65 mm v 48 mm; nighttime: 59 mm v 47 mm). Although there were only two dropouts in the study reported by Terg et al. (30), 52 adverse effects were described—which affected 20 subjects (2.6 per subject). In the Wolfhagen et al. study there were no dropouts, but 23 adverse effects in 8 subjects (2.9 per subject).

In three of the five cited naltrexone studies, vertigo was documented in 19–50% of patients. This needs to be borne in mind in clinical practice, as vertigo is a risk factor for falls (36) and represents a widespread problem in patients with advanced cancers, for example (37). The use of naltrexone in palliative care patients is risky because of a possible loss of analgesia. The opioid antagonist methylnaltrexone could be an alternative, which does not pass the blood-brain barriers (unlike naltrexone) and therefore does not impair the centrally mediated analgesic effect of opioids (38).

HIV patients (n = 10)

A significant difference between the tested substances existed in the study by Smith et al. only between the indometacin group (median: 3) and the triamcinolone group (median: 1). As each group included only 10 patients, it is difficult to draw any firm conclusions about the effect. Furthermore, the fact that indigestion was reported in four cases and abdominal pain in three cases is probably worth a critical review (31).

All substances that were found to be effective were used off-label in the studies. In the area of palliative medical care, such off-label use is a typical phenomenon and applies to up to 40% of prescribed medications (39).

Conclusion

This systematic review investigates the effectiveness of pharmacological interventions for pruritus in adult palliative care patients with malignant and non-malignant disorders. The guideline from the German Dermatological Society provides a clinically oriented perspective for the treatment of chronic pruritus (40). The present study describes the effectiveness of:

  • Paroxetine in general palliative care patients
  • Gabapentin, nalfurafine, cromoglicate, and naltrexone in patients with uremic pruritus
  • Flumecinol, rifampicin, and naltrexone in patients with cholestatic pruritus.

Owing to methodological problems of the available studies, the results of this review and their generalizability will have to be interpreted with caution. Because of the diversity of palliative care patients with pruritus, any therapeutic approach needs to be carefully considered. The effect of methylnaltrexone and the other substances presented should ideally be investigated in further high quality RCTs.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Acknowledgement
The authors thank Ms Sabine Buroh, librarian at the University Medical Center Freiburg, for her help with the electronic database search.

Manuscript received on 16 June 2014, revised version accepted on
16 September 2014.

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
Dipl. Sportwiss. Waldemar Siemens
Universitätsklinikum Freiburg
Klinik für Palliativmedizin
Robert-Koch-Str. 3
79106 Freiburg, Germany
waldemar.siemens@uniklinik-freiburg.de

@eFigure and eTable:
www.aerzteblatt-international.de/14m0863

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Department of Palliative Care, Freiburg University Medical Center, Freiburg:
Dipl. Sportwiss. Siemens, Dipl.-Theol. Dipl.-Caritaswiss. Dipl.-Soz.Päd. Xander, Prof. Dr. med. MSc Becker
Freiburg University Medical Center, German Cochrane Center, Freiburg:
Dr. med. Meerpohl, Prof. Dr. rer. nat. Antes
* These two authors have contributed equally to the manuscript and share first authorship.
Key messages
Selection of analyzed studies
Selection of analyzed studies
Figure
Selection of analyzed studies
Substances for uremic pruritus: randomized, controlled studies from updated search
Substances for uremic pruritus: randomized, controlled studies from updated search
Table 1
Substances for uremic pruritus: randomized, controlled studies from updated search
Effectiveness of substances for pruritus
Effectiveness of substances for pruritus
Table 2
Effectiveness of substances for pruritus
Assessment of bias risk
Assessment of bias risk
eFigure
Assessment of bias risk
Clinically relevant pharmacological interventions for pruritus
Clinically relevant pharmacological interventions for pruritus
eTable
Clinically relevant pharmacological interventions for pruritus
1.Rothmann S: Physiology of itching. Physiol Rev 1941; 21: 357–81.
2.Bernhard JD: Itch and pruritus: what are they, and how should
itches be classified? Dermatol Ther 2005; 18: 288–91. CrossRef MEDLINE
3.Summey B: Pruritus. In: Walsh DT CAFRea (ed.): Palliative Medicine. Philadelphia: Saunders Elsevier 2009.
4.Zylicz Z, Twycross R, Jones AE: Pruritus in advanced disease. New York: Oxford University Press 2004. CrossRef
5.Langner MD, Maibach HI: Pruritus measurement and treatment. Clin Exp Dermatol 2009; 34: 285–8. CrossRef MEDLINE
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