Ventilatory Responses to Hypoxia and Hypercapnia in Stable Methadone Maintenance Treatment Patients

doi:10.1378/chest.128.3.1339

Chest

Volume 128, Issue 3, September 2005, Pages 1339-1347

https://doi.org/10.1378/chest.128.3.1339 Get rights and content

Rationale

Methadone is a long-acting μ-opioid and is an effective treatment for heroin addiction. Opioids depress respiration, and patients receiving methadone maintenance treatment (MMT) have higher mortality than the general population. Few studies have investigated ventilatory responses to both hypercapnia and hypoxia in these patients.

Study objectives

We measured hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) and investigated possible factors associated with both in clinically stable patients receiving MMT.

Design and setting

Patients receiving long-term, stable doses of methadone recruited from a statewide MMT program, and normal, non-opioid-using subjects matched for age, sex, height, and body mass index were studied with HCVR and HVR.

Results

Fifty MMT patients and 20 normal subjects were studied, and significantly decreased HCVR and increased HVR were found in MMT patients compared to normal subjects (HCVR [mean ± SD], l.27 ± 0.61 L/min/mm Hg vs 1.64 ± 0.57 L/min/mm Hg [p = 0.01]; HVR, 2.14 ± 1.58 L/min/% arterial oxygen saturation measured by pulse oximetry [Spo₂] vs 1.12 ± 0.7 L/min/% Spo₂ [p = 0.008]). Respiratory rate and not tidal volume changes were the major physiologic responses contributing to both HCVR and HVR differences between the groups. Variables associated with HCVR in the MMT patients are as follows: obstructive sleep apnea/hypopnea index (t = 5.1, p = 0.00001), Paco₂ (t = − 3.6, p = 0.001), body height (t = 2.6, p = 0.01) and alveolar-arterial oxygen pressure gradient (t = 2.5, p = 0.02). Variables associated with HVR in MMT patients are body height (t = 3.2, p = 0.002) and Paco₂ (t = − 2.8, p = 0.008).

Conclusions

Stable long-term MMT patients have blunted central and elevated peripheral chemoreceptor responses. The mechanisms and clinical significance of these findings need further investigation.

Section snippets

Materials and Methods

This study forms part of a project assessing sleep architecture and sleep-disordered breathing in stable MMT patients.

Demographics

Fifty stable MMT patients (25 men and 25 women) and 20 normal, nonopioid-using subjects (10 men and 10 women) matched by age, sex, height, and body mass index were studied. Demographic data and blood toxicology results are shown in Table 1. All MMT patients had methadone in their blood. Five patients used a selective serotonin reuptake inhibitor, one patient used a selective noradrenaline reuptake inhibitor, and one patient used a monoamine oxidase inhibitor antidepressant.

HCVR and HVR

MMT patients had

Discussion

To our knowledge, this is the first cross-sectional study to investigate both HCVR and HVR in a large cohort of stable MMT patients receiving methadone for ≥ 2 months, and to compare the data with that from normal, non-opioid-using normal subjects. We found that HCVR and HVR are significantly different in the subject groups. Interestingly, change in RR was the major component responsible for the differences in the ventilatory responses to both hypoxia and hypercapnia between the patients and

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For instance, morphine decreases the hypercapnic, as well as the hypoxic ventilatory response, in healthy volunteers (Weil et al., 1975). Methadone also blunts the hypoxic ventilatory response in patients (Teichtahl et al., 2005). However, in patients with mild-to-severe sleep apneas, morphine may improve breathing disorders by slightly blunting chemoreflexes (Wang et al., 2013).
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Central sleep apnea (CSA) is associated with increased mortality, especially in patients with underlying cardiac diseases. However, optimal treatment of CSA is still under debate. While there is consensus on optimal treatment of any underlying cardio- or cerebrovascular disease, internal or neurologic comorbidities, the impact of positive airway pressure therapy (PAP) is less clear. Continuous, automatic and bilevel PAP have been shown to reduce CSA by 50%. Adaptive servoventilation is the optimal algorithm to normalize central breathing disturbances including periodic breathing. For today, it should be reserved to symptomatic patients with a left ventricular ejection fraction ≥ 45% if CSA is predominant.

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Chest

Clinical InvestigationsVentilatory Responses to Hypoxia and Hypercapnia in Stable Methadone Maintenance Treatment Patients

Rationale

Study objectives

Design and setting

Results

Conclusions

Section snippets

Materials and Methods

Demographics

HCVR and HVR

Discussion

Am J Med

Chest

Biol Psychiatry

Psychiatry Res

Respir Physiol

Pharmacol Biochem Behav

Am J Med

Respir Physiol

How many dependent heroin users are there in Australia?

Med J Aust

NIH Consensus Conference. Effective medical treatment of opiate addiction. National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction

JAMA

Methadone maintenance treatment and other opioid replacement therapies

Retention in methadone maintenance and heroin addicts’ risk of death

Addiction

All-cause mortality rate and risk of dying in methadone maintenance treatment in New South Wales in 1990–95. International Opioid Overdose Symposium

Kinetics of intravenous and intramuscular morphine

Clin Pharmacol Ther

The effect of ageing on plasma pethidine concentration

Br J Clin Pharmacol

Delayed respiratory depression after alfentanil

Anesthesiology

Acute respiratory arrest and rigidity after anesthesia with sufentanil: a case report

Anesthesiology

Intravenous opioid anaesthetics

Regulation of breathing: drug effects

Disruption of the rhythmic activity of the medullary inspiratory neurons and phrenic nerve by fentanyl and reversal with nalbuphine

Anesthesiology

Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man

N Engl J Med

Influences of morphine on the ventilatory response to isocapnic hypoxia

Anesthesiology

Effects of intrathecal morphine on the ventilatory response to hypoxia

N Engl J Med

Chronic hypercapnia during methadone maintenance

Am Rev Respir Dis

Respiratory consequences of methadone: the response to added resistance to breathing

Am Rev Respir Dis

Clinical Investigations
Ventilatory Responses to Hypoxia and Hypercapnia in Stable Methadone Maintenance Treatment Patients