Interventions for managing taste disturbances

Sumanth Kumbargere Nagraj; Renjith P George; Naresh Shetty; David Levenson; Debra M Ferraiolo; Ashish Shrestha

doi:10.1002/14651858.CD010470.pub3

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Zinc versus placebo, outcome: 1.1 Taste acuity improvement ‐ Patient‐reported outcome.

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Figure 4

Forest plot of comparison: 1 Zinc versus placebo, outcome: 1.2 Taste acuity improvement ‐ Objective outcome ‐ Continuous data.

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Figure 5

Forest plot of comparison: 1 Zinc versus placebo, outcome: 1.5 Taste acuity improvement ‐ Objective outcome ‐ Dichotomous.

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Analysis 1.1

Comparison 1 Zinc versus placebo, Outcome 1 Taste acuity improvement ‐ Patient‐reported outcome.

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Analysis 1.2

Comparison 1 Zinc versus placebo, Outcome 2 Taste acuity improvement ‐ Objective outcome ‐ Continuous data.

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Analysis 1.3

Comparison 1 Zinc versus placebo, Outcome 3 Taste acuity improvement for different taste sensations.

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Analysis 1.4

Comparison 1 Zinc versus placebo, Outcome 4 Taste acuity improvement ‐ Cross‐over study.

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Analysis 1.5

Comparison 1 Zinc versus placebo, Outcome 5 Taste acuity improvement ‐ Objective outcome ‐ Dichotomous.

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Analysis 1.6

Comparison 1 Zinc versus placebo, Outcome 6 Adverse events.

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Analysis 2.1

Comparison 2 Acupuncture versus sham control, Outcome 1 Taste discrimination.

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Summary of findings for the main comparison. Zinc compared to placebo for the management of taste disturbances

Zinc compared to placebo for the management of taste disturbances
Patient or population: patients with taste disturbances Setting: secondary and tertiary hospitals Intervention: zinc Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with zinc
Taste acuity improvement (patient‐reported outcome) assessed with VAS/questionnaire where improvement in dysgeusia is defined as more than 5% improvement in the VAS scores for a mean follow‐up period of 3 months	Study population ‐ zinc‐deficient/idiopathic taste disorder		1.40 (0.94 to 2.09)	119 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^{1, 2, 3}	There is a 40% relative increase in taste acuity improvement (patient‐reported outcome) in patients taking zinc when compared to placebo with a CI of 6% decrease to 109% increase of taste acuity
	407 per 1000	569 per 1000 (382 to 850)
Taste acuity improvement (objective outcome ‐ continuous data) assessed with filter paper strip and filter paper disk methods for a mean follow‐up period of 3 months	‐	SMD 0.44 higher (0.23 higher to 0.65 higher)	‐	366 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^{3, 4, 5}	The standardised mean difference for taste acuity improvement in the zinc intervention group is 0.44 higher than the placebo group
Taste acuity improvement (objective outcome ‐ dichotomous data) assessed with filter paper disk and Henkin's 3‐drop stimulus method for a mean follow‐up period of 3 months	Study population ‐ zinc‐deficient/idiopathic taste disorder		RR 1.42 (1.09 to 1.84)	292 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^{3, 6, 7}	There is a 42% relative improvement in taste acuity in patients taking zinc when compared to placebo with a CI of 9% to 84% increase of taste acuity
	435 per 1000	618 per 1000 (475 to 801)
Cross‐over trial ‐ taste detection assessed with Henkin's method for a follow‐up period of 6 months	The mean taste detection was 7.5	MD 2.50 higher (0.93 higher to 4.07 higher)	‐	14 (1 RCT)	⊕⊝⊝⊝ VERY LOW^{3, 7, 8}	The mean difference for taste detection in the intervention group is 2.50 higher than the placebo group
Cross‐over trial ‐ taste recognition assessed with Henkin's method for a follow‐up period of 6 months	The mean taste recognition was 16	MD 3.00 higher (0.66 higher to 5.34 higher)	‐	14 (1 RCT)	⊕⊝⊝⊝ VERY LOW^{3, 7, 8}	The mean difference for taste recognition in the intervention group is 3.00 higher than placebo group
Adverse events ‐ follow‐up range 12 weeks to 18 weeks	Study population ‐ zinc‐deficient/idiopathic taste disorder and taste disorder secondary to chronic renal failure		5.20 (0.90 to 30.19)	335 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^{3, 7, 8}	Risk of 1 per 1000 assumed in placebo group (as it was 0) There is 420% relative increase in the adverse events in patients taking zinc compared to placebo with 95% CI of 10% decrease to 2919% increase in adverse events
	6 per 1000	31 per 1000 (5 to 180)
^*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio; SMD: standardised mean difference; VAS: visual analogue scale.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Unclear randomisation and high risk of bias due to attrition in Sakai 2002. Downgraded by 1 level. ²The confidence interval of the effect estimate indicates no difference as well as appreciable benefit with zinc. Downgraded by 1 level. ³We know a trial with unpublished results which was not shared by the investigators. Hence we suspect publication bias and have downgraded by 1 level. ⁴Unclear selection bias in two trials (Ikeda 2013; Sakagami 2009). Downgraded by 1 level. ⁵Wide confidence intervals in all 3 included trials (Heckmann 2005; Ikeda 2013; Sakagami 2009). Downgraded by 1 level. ⁶High risk of bias in Sakai 2002 due to attrition bias. Downgraded by 1 level. ⁷Wide confidence intervals in the trial. Downgraded by 1 level. ⁸High risk of bias due to incomplete outcome data and other reasons explained in other bias. Downgraded by 1 level.

Summary of findings for the main comparison. Zinc compared to placebo for the management of taste disturbances

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Summary of findings 2. Acupuncture compared to sham control for the management of taste disturbances

Acupuncture compared to sham control for the management of taste disturbances
Patient or population: idiopathic dysgeusia combined with hypogeusia Setting: tertiary healthcare centre (university clinic) Intervention: acupuncture Comparison: sham control
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with sham (control)	Risk with acupuncture
Taste discrimination assessed with 32 taste strips with a follow‐up of 8 weeks	The mean taste discrimination was 14.7	MD 2.80 higher (1.18 lower to 6.78 higher)	‐	37 (1 RCT)	⊕⊕⊝⊝ VERY LOW^{1, 2}	The mean difference for taste discrimination in the acupuncture group is 2.80 higher than the sham group
*^The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT:** randomised controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Brandt 2008 is a single‐blind trial with high risk of performance bias. Downgraded by 2 levels. ²The confidence interval of the effect estimate indicates no difference as well as appreciable benefit with acupuncture. Downgraded by 1 level.

Summary of findings 2. Acupuncture compared to sham control for the management of taste disturbances

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Table 1. Ikeda 2013 ‐ Continuous data

Outcome	Group A			Group B			Time when measured
Outcome	Mean^*	SD	n	Mean^*	SD	n	Time when measured
Change of the mean 4 basic taste sensitivity scores from baseline	‐0.52	0.68	108	‐0.47	0.61	111	4 weeks
	‐0.90	0.85	108	‐0.67	0.73	111	8 weeks
	‐1.17	0.93	108	‐0.85	0.75	111	12 weeks
	‐1.28	0.94	108	‐0.97	0.76	111	4 weeks after treatment
^*Minus change score means better by filter paper disc method by Tomita. SD = standard deviation.

Table 1. Ikeda 2013 ‐ Continuous data

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Table 2. Ikeda 2013 ‐ Dichotomous data

Outcome	Group A events (Improved)	Group A total	Group B events	Group B total	Time when measured
Improved/not improved	60	108	48	111	12 weeks

Table 2. Ikeda 2013 ‐ Dichotomous data

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Table 3. Sakagami 2009 ‐ Continuous data

Outcome	Group A (Placebo) n = 27		Group B (17 mg zinc) n = 27		Group C (34 mg zinc) n = 25		Group D (68 mg zinc) n = 28		Time when measured
Secondary outcome	Mean	SD	Mean	SD	Mean	SD	Mean	SD	12 weeks
Mean filter paper disk test scores (filter paper disk)	4.095	1.148	4.350	1.030	3.448	0.928	3.454	1.138	─
Mean serum zinc level	1.8	12.7	5.7	13.5	11.4	16.6	20.6	21.3	─
‐	Group A		Group B		Group C		Group D		─
Increase in the average score of subjective symptoms	0.6		0.9		1.2		1.0		─
SD = standard deviation.

Table 3. Sakagami 2009 ‐ Continuous data

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Table 4. Sakagami 2009 ‐ Dichotomous data

Primary outcome: quantitative analysis of taste perception using filter paper disk method	Event (success) Cured + improved	No event (fail) Unchanged, neither cured nor improved nor worsened; aggravated	Total
Experimental intervention (17 mg zinc)	S_E = 14	F_E = 13	N_E = 27
Control intervention (placebo)	S_C = 17	F_C = 10	N_C = 27
RR = 0.824; OR = 0.634; RD = 0.447
Experimental intervention (34 mg zinc)	S_E = 20	F_E = 5	N_E = 25
Control intervention (placebo)	S_C = 17	F_C = 10	N_C = 27
RR = 0.318; OR = 2.353; RD = 0.17
Experimental intervention (68 mg zinc)	S_E = 25	F_E = 3	N_E = 28
Control intervention (placebo)	S_C = 17	F_C = 10	N_C = 27
RR = 1.418; OR = 4.902; RD = 0.263
OR = odds ratio: odds of event in experimental group/odds of event in control group; RD = risk difference: risk of event in experimental group/risk of event in control group; RR = risk ratio: risk of event in experimental group/risk of event in control group.

Table 4. Sakagami 2009 ‐ Dichotomous data

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Table 5. Sakai 2002

Filter paper disk method	Event (success) Improved (+ cured)	No event (fail) Unchanged	Total (n = 73)
Experimental intervention (zinc picolinate)	S_E = 28	F_E = 9	N_E = 37
Control intervention (placebo)	S_C = 16	F_C = 20	N_C = 36
RR = 1.703; OR = 3.889; RD = 0.312
Experimental intervention (zinc picolinate)	S_E = 22	F_E = 12	N_E = 34
Control intervention (placebo)	S_C = 18	F_C = 17	N_C = 35
RR = 1.258 ; OR = 1.732; RD = 0.133
OR = odds ratio: odds of event in experimental group/odds of event in control group; RD = risk difference: risk of event in experimental group/risk of event in control group; RR = risk ratio: risk of event in experimental group/risk of event in control group.

Table 5. Sakai 2002

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Table 6. Heckman 2005 ‐ Continuous data

Outcome	Group A (zinc treatment)			Group B (placebo)			Time when measured
Outcome	Mean	SD	n	Mean	SD	n	At the end of 3 months
Primary outcome	─
Taste test (32‐filter paper strip method by Mueller 2003)	25.7	6.5	26	21.2	5.7	24	─
Self‐rated impairment in % (VAS scale of 10 cm length equivalent to 100%; 0 to 10; 0 = no impairment; 10 = extremely impaired)	45.0	4.4	26	43.8	3.6	24	─
Secondary outcome	─
Beck Depression Inventory (BDI)	7.5	7.0	26	11.3	10.9	24	─
Zerssen Mood Scale (ZMS)	10.7	7.5	26	18.8	14.6	24	─
Zinc in serum (µg/dL)	81.53	19.61	26	72.01	10.22	24	─
SD = standard deviation; VAS = visual analogue scale.

Table 6. Heckman 2005 ‐ Continuous data

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Table 7. Heckman 2005 ‐ Dichotomous data

Type of intervention	Event (success) Improved	No event (fail)	Total
Experimental intervention (zinc)	S_E = 13	F_E = 13	N_E = 26
Control intervention	S_C = 6	F_C = 18	N_C = 24
RR = 2; OR = 3; RD = 0.25
OR = odds ratio: odds of event in experimental group/odds of event in control group; RD = risk difference: risk of event in experimental group/risk of event in control group; RR = risk ratio: risk of event in experimental group/risk of event in control group.

Table 7. Heckman 2005 ‐ Dichotomous data

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Table 8. Brandt 2008

Outcome	Group A				Group B				Time when measured
	Mean	SD^*	n = 17		Mean	SD^*	n = 20
Taste discrimination	11.7 (before)/ 17.5 (after)	4 (before)/ 7 (after)	─		11.9 (before)/ 14.7(after)	5 (before)/ 5 (after)	─		Before and after treatment
Quality of life	Not estimable (changes per group only given for each of the 5 individual questions of the questionnaire, but no combined score/analysis stated). Only information given: "both treatments resulted in an increased quality of life, however, no statistically significant difference could be found"								Before and after treatment
Depressive symptoms	11 (before)/ 6 (after)^*	5 (before) / 4 (after)^*		─	10.5 (before)/ 10 (after)^*	7 (before)/ 7 (after)^*		─	Before and after treatment
	Quote: "The psychological well‐being of the intervention groups increased for 94.1% of all patients in the intervention group, but only for 60% of patients in the control group. This difference was statistically significant"
Subjective well‐being	16 (before)/ 12 (after)^*	10 (before)/ 7 (after)^*		─	20 (before)/ 18 (after)^*	9 (before)/ 14 (after)^*		─	Before and after treatment
	Quote: "58.8% of all patients in the intervention group felt better, whereas only 45% of all patients in the control group felt better. This difference was not statistically significant"
^*Only given in graph ‐> estimated from graph. SD = standard deviation.

Table 8. Brandt 2008

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Table 9. Sakai 2002 ‐ Adverse events

Outcome

Group A ‐ Zinc picolinate

events

Group A total

Group B ‐ Placebo

events

Group B total

Time when measured

Adverse events

3 months

Table 9. Sakai 2002 ‐ Adverse events

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Table 10. Sakagami 2009 ‐ Adverse events

Outcome	Group A ‐ 17 mg zinc events	Group A total	Group B ‐ 34 mg zinc events	Group B total	Group C ‐ 68 mg zinc events	Group C total	Group D ‐ Placebo events	Group D total	Time when measured
Adverse events	5	27	6	25	7	28	3	27	12 weeks

Table 10. Sakagami 2009 ‐ Adverse events

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Comparison 1. Zinc versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Taste acuity improvement ‐ Patient‐reported outcome Show forest plot	2	119	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.94, 2.09]

2 Taste acuity improvement ‐ Objective outcome ‐ Continuous data Show forest plot	3	366	Std. Mean Difference (IV, Random, 95% CI)	0.44 [0.23, 0.65]

3 Taste acuity improvement for different taste sensations Show forest plot	1	88	Mean Difference (IV, Random, 95% CI)	119.43 [14.48, 224.39]

3.1 Salt	1	22	Mean Difference (IV, Random, 95% CI)	285.0 [238.75, 331.25]
3.2 Sweet	1	22	Mean Difference (IV, Random, 95% CI)	190.0 [142.36, 237.64]
3.3 Sour	1	22	Mean Difference (IV, Random, 95% CI)	10.0 [‐16.43, 36.43]
3.4 Bitter	1	22	Mean Difference (IV, Random, 95% CI)	2.4 [2.14, 2.66]
4 Taste acuity improvement ‐ Cross‐over study Show forest plot	1	28	Mean Difference (IV, Random, 95% CI)	2.66 [1.35, 3.96]

4.1 Taste detection	1	14	Mean Difference (IV, Random, 95% CI)	2.5 [0.93, 4.07]
4.2 Taste recognition	1	14	Mean Difference (IV, Random, 95% CI)	3.00 [0.66, 5.34]
5 Taste acuity improvement ‐ Objective outcome ‐ Dichotomous Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Idiopathic and zinc‐deficient taste disorders	2	292	Risk Ratio (M‐H, Random, 95% CI)	1.42 [1.09, 1.84]
5.2 Taste disorder secondary to chronic renal failure	1	24	Risk Ratio (M‐H, Random, 95% CI)	25.00 [1.65, 379.57]
6 Adverse events Show forest plot	3	335	Risk Ratio (M‐H, Random, 95% CI)	5.20 [0.90, 30.19]

Comparison 1. Zinc versus placebo

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Comparison 2. Acupuncture versus sham control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Taste discrimination Show forest plot	1	37	Mean Difference (IV, Random, 95% CI)	2.80 [‐1.18, 6.78]

Comparison 2. Acupuncture versus sham control

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