Table 1.

Characteristics of studies investigating the effect of morphine on dyspnea

Reference	Study type	Study group	Drug, dose, and route of administration	Equivalent oral morphine dose	Measures: primary outcome (secondary outcome)	Results
Johnson et al., British Med. J. 1983 (26)	Randomized, double-blinded, placebo-controlled crossover study	17 COPD patients and one with pulmonary fibrosis.	Oral 15 mg dihydrocodeine t.i.d. for 1 week and on alternate days for 1 week (i.e. treatment for 2 weeks).	3 mg	100 mm VAS score for dyspnea; daily and during treadmill test (PEFR, number of steps, VAS score for breathlessness, constipation, nausea, anxiety, and drowsiness at home. FEV1, FVC, and distance and VAS score for dyspnea at treadmill).	Reduced dyspnea both weekly and on alternate days (p<0.001). Longer walk distance after 1 week of treatment (p<0.05). Reduced dyspnea at treadmill test.
Eiser et al., Eur Respir J 1991 (27) First studya	Randomized, double-blinded, placebo-controlled crossover study	18 COPD patients.	Oral linctus of diamorphine 2.5 mg or 5 mg as 5 ml for 2 weeks each.	10 or 20 mg	100 mm VAS scale for dyspnea; daily and at 6MWT and treadmill walk on study day (VAS scale for drowsiness, overall well-being, and number of times awakening during the night because of dyspnea. Spirometry, blood gases, plasma level of morphine. Walk distance at 6MWT, time on treadmill.)	No significant difference in dyspnea at home or related to exercise tests.
Second studya	Randomized, double-blinded, placebo-controlled, crossover study	10 COPD patients.	Oral linctus of diamorphine 7.5 mg.	30 mg	100 mm VAS scale for dyspnea at 6MWT (spirometry, blood gases, plasma level of morphine, distance at 6MWT).	No statistical significance in changes, but trend for both dyspnea and walking distance to improve on morphine.
Light et al., Chest 1996 (23) First studya	Randomized, double-blinded, placebo-controlled crossover study	Seven COPD patients.	Oral solution of morphine 30 mg alone, 30 mg morphine and 25 mg MP or 30 mg morphine and 10 mg MPC.	30 mg	Modified Borg score for dyspnea during the last 30 sec of every power output at the cycle ergometer test. (Subjective feelings with Bond scale, visual vigilance, motor speed and spirometry. Expired gas analysis, HR, and RR.)	Improved dyspnea with MP treatment (except at VO2max), not with M alone. Significant increase in VO2max and decrease in VO2 and VCO2 after MP.
Second study	Randomized, double-blinded, placebo-controlled crossover study	Nine COPD patients.	Oral solution of 25 mg promethazine (P) or 30 mg morphine and 25 mg promethazine (MP).	30 mg		No significant difference in dyspnea. Significant increase in VO2max, VCO2max, VE, and VT.
Poole et al., Am. J. Respir. Crit. Care Med. 1998 (19)	Randomized, double-blinded, placebo-controlled, crossover study	16 COPD patients.	Oral sustained-release morphine sulfate 10 mg tablets – titrated from 10 mg once a day to maximally 20 mg twice a day for 6 weeks.	20 mg×2	Chronic Respiratory Disease Questionnaire (QRQ) subscale for dyspnea at rest both at home twice daily and at study center in the beginning and end of each 6-week treatment period (FEV1, FVC, distance at 6MWT, sat − O2, and side effects).	No significant improvement in dyspnea. Distance at 6MWT decreased during morphine treatment, but increased during placebo.
Abernethy et al., British Med. J 2003 (21)	Randomized, double-blinded, placebo-controlled crossover study	38 COPD patients, 10 not specified.	Oral sustained-release morphine sulfate q.d. 20 mg for 4 days.	5 mg	100 mm VAS scale for dyspnea in the evening at rest (morning dyspnea, exercise tolerance, RR, BP, HR, sat-O2, disturbance of sleep. Categorical scale for 7 items.)	Reduced dyspnea in the morning (p=0.011) and evening (p=0.006). Less sleep disturbance (p=0.039).
Currow et al., J. of Pain and Symptom Management 2011 (17)	Open-label, Phase II dose increment study followed by Phase IV effectiveness and safety study	83 outpatients (54% with COPD, 12% with ILD, the rest with different diagnoses). 52 joined the Phase IV study.	Oral morphine: initially 10 mg daily raised to maximally 30 mg daily for non-responders for 3 months if no side effects.	10–30 mg	100 mm VAS scale for dyspnea twice daily at rest (quality of life, number of dose changes, dose at 3 months, side effects).	Reduced dyspnea in both phases. Benefit maintained for >3 months for one-third of patients. Decreased VAS score with 17.1 mm (SD 11.6).
Allen et al., Pall. Med. 2005 (14)	Non-randomized, open case study	11 IPF patients.	Subcutaneously injected q.d. 2.5/5 mg diamorphine (5 mg for patients >60 kg). Oral morphine as long-term treatment. Mean survival of 5 weeks after starting opioids.	10 or 20 mg	100 mm VAS score for dyspnea at rest (HR, BP, RF, sat-O2).	Reduced dyspnea (p<0.0001).
Young et al., Thorax 1989 (18)	Randomized, double-blind, placebo-controlled crossover study	11 patients (2 IPF, 9 COPD).	Nebulized 5 mg of morphine (1 g/ml).	5 mg	No dyspnea score used. Dyspnea only recorded as a limiting symptom at cycle ergometer test (spirometry).	Dyspnea maintained to be the limiting symptom in all three tests. Mean endurance time increased with morphine.
Harris-Eze et al., Am. J. Respir. Crit. Care Med. 1995 (22)	Randomized double-blinded, placebo-controlled study	Six ILD patients (Three IPF).	Nebulized morphine 2.5 mg and 5.0 mg.	2.5 or 5 mg	Modified Borg scale for dyspnea at end exercise after cycle ergometer test (HR, ECG, sat-O2, inspiratory and expiratory volumes, expired O2, and CO2).	No significant differences in any of the measured variables including dyspnea.
Masood et al., Thorax 1995 (28)	Randomized, double-blinded, placebo-controlled, crossover study	12 COPD patients.	Combinations of nebulization and i.v. treatment in five regimens: 1) placebo, 2) nebulized morphine 10 mg, 3) nebulized morphine 25 mg, 4) i.v. morphine 1.0 mg, and 5) i.v. morphine 2.5 mg. With 2 + 3 i.v. placebo and with 4 + 5 nebulized placebo was given.	10 or 25 mg, 3.0 or 7.5 mg	100 mm VAS scale for dyspnea at rest and during cycle ergometer test (oxygen consumption (VO2), carbon dioxide production (VCO2), FEV1, VC, PEFR, and sat-O2. HR, RR, BP, exercise endurance, symptom limitation, and plasma morphine level.)	No significant change in dyspnea. No change in exercise endurance or ventilation.
Leung et al., Thorax 1996 (25)	Randomized, double-blinded, placebo-controlled, crossover study	Nine COPD patients and one ILD patient.	Nebulized morphine 5 mg (1 g/ml).	5 mg	Modified Borg score for dyspnea every minute during exercise on cycle ergometer (sat-O2, RR, MV, and ECG, dose of nebulized morphine).	No significant difference in dyspnea or power output.
Jankelson et al., Eur. Respir. J. 1997 (24)	Randomized double-blinded, placebo-controlled, crossover study	16 COPD patients.	Nebulized morphine sulfate 20 or 40 mg.	20 or 40 mg	Modified Borg score for dyspnea at 6MWT (sat − O2, HR, walked distance. Spirometry (FEV1 and FVC) and measure of blood gases at baseline. Plasma level of morphine).	No significant change in dyspnea or other parameters.
Noseda et al., Eur. Respir. J. 1997 (20)	Randomized, double-blinded, placebo-controlled crossover study	17 patients (11 COPD, 1 cancer, 1 IPF, 1 heart disease).	Nebulized morphine given in four settings: morphine 10 mg×2 (with and without O2), morphine 20 mg with oxygen or saline with oxygen. Oxygen was given 3 out of 4 days.	10 or 20 mg	Bipolar (−100%, +100%) VAS scale for dyspnea at rest (sat-O2, RR).	No significant difference in dyspnea. No difference in response to 10 mg morphine given with/without oxygen.
Jensen et al., J. Pain Symp. Man. 2012 (29)	Single center, randomized, double-blind, placebo-controlled crossover study	12 COPD patients.	Nebulized fentanyl citrate 50 mcg (single dosage).	5 mg	Dyspnea intensity at isotime during exercise and EET (PFT, cardiorespiratory, and breathing pattern parameters measured at rest, isotime, and at end of exercise).	No significant change in dyspnea intensity. Significantly increased exercise endurance time.

^aThe studies by Eiser and Light each consisted of two different studies and they were therefore evaluated separately.

COPD: chronic obstructive lung disease; t.i.d.: three times a day; VAS: visual analog score; FEV1: forced expiratory volume in 1 sec; FVC: forced vital capacity; PEFR: peak expiratory flow rate; 6MWT: 6-min walk test; MP: promethazine; MPC: prochlorperazine; HR: heart rate; RR: respiratory rate; VO₂max: maximal oxygen consumption; VE: minute ventilation; VCO₂max: maximal CO₂ production; VT: tidal volume; sat-O₂: arterial oxygen saturation; q.d.: once daily; BP: blood pressure; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; RF: respiratory frequency; ECG: electrocardiogram; i.v.; intravenous; PFT: pulmonary function test; SE: standard error.