Morphine Inhalation by Cancer Patients: A Comparison of Different Nebulization Techniques Using Pharmacokinetic, Spirometric, and Gasometric Parameters

Article Outline

• Abstract
• Introduction
• Methods
  • Patients and Study Protocol
  • Equipment and Inhalation Systems
  • Inhalation Procedure
  • Analytical Procedures
    • Extraction of Morphine and Its Metabolites From Blood and Urine
    • Statistical and Pharmacokinetic Analysis
• Results
  • Adverse Effects
  • Pharmacokinetics
  • Urine Excretion
  • Spirometry
  • Gasometry
• Discussion
• References
• Copyright

Abstract 

Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System-Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2–5μm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5–2μm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6±2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8±8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20–40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs.

Key Words: Pneumodosimetric nebulization, morphine pharmacokinetics, morphine deposition, cancer patients, morphine-6-glucuronide, morphine-3-glucuronide

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Introduction 

A systematic review of 18 randomized controlled trials proved the efficacy of oral and parenteral but not nebulized opioids in the treatment of breathlessness.¹ This is in contrast to anecdotal and preliminary controlled evidence that repeatedly suggested the positive effect of opioids in the palliation of breathlessness in patients with advanced cancer and cystic fibrosis.², ³, ⁴, ⁵ All of the trials for nebulized opioids reviewed by Jennings et al.¹ were carried out without standardization of the inhalation method, without basic knowledge of the localization of receptors in the respiratory tract, and without knowing whether the aerosolized opioids were reaching the receptors or not. From a clinical point of view, it is still not known whether opioids act locally in the respiratory tract, systemically on the remote receptors in the central nervous system, or at both sites. Opioids, at least in vitro, inhibit the release of proinflammatory neurotransmitters from sensory nerve endings and reverse the contraction of isolated bronchi and diminish mucus production.⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³ Such effects would be useful in the treatment of breathlessness.

Visualization studies have shown the expression of opioid-binding sites in adult rat and human lung homogenate and opioid receptor immunoreactivities in the alveolar epithelial cells in fetal mouse lung.¹⁴, ¹⁵, ¹⁶, ¹⁷ Immunohistochemical visualization by our group of opioid receptors in the human respiratory tract revealed their presence in tracheal and bronchial epithelium and in sensory nonmyelinated fibers.¹⁸ These nerve terminals were arborizing close to the superficial layer of normal bronchial epithelium, while in the alveoli opioid receptors were almost exclusively localized in macrophages. These observations suggest that aerosolized opioids may act differently depending on the droplet size and deposition. Thus, the choice and standardization of inhalation method may be critical for the outcome, independent of the study design and power.

One of us (Z. P.) developed two different protocols for pneumodosimetric nebulization.¹⁹ Both methods were described by us recently in detail.²⁰ These protocols are a combination of a pneumodosimetric (Bronchial Control Treatment System [BCTS]) method with the application of two different nebulizers: Sidestream (S) and Micro Cirrus (MC). Sidestream usually produces particles of 2–5μm in diameter, whereas MC produces smaller particles of 0.5–2μm.²⁰ In the BCTS-Sidestream (BCTS-S) method, morphine aerosol is injected into the inspired air at a late phase in each inspiration defined as effective. In the BCTS-MC method, morphine aerosol is administered into the early phase of inspiration and, similar to the BCTS-S method, only if this inspiration is vigorous. As a result of this, with the BCTS-S method, the main deposition is expected in the trachea and the bronchi, whereas with the BCTS-MC method, preferential deposition is expected in the alveoli. Another difference is that the dose of aerosol in the BCTS-S method is administered in a much shorter time than with the BCTS-MC method. In both pneumodosimetric methods, the dose of morphine administered is known exactly by the measurement taken at the mouthpiece, and the expected losses through adsorption on the surface of the equipment are negligible.

In contrast, in typical pneumatic methods, approximately 40%–50% of the nebulized drug is trapped inside the chamber and, thus, is unavailable to the patient.²⁰ Additionally, about 25% of the aerosol produced may be wasted during expiration. In both BCTS methods, aerosol is administered to the first (BCTS-MC) or to the third (BCTS-S) quarter of inspired volume; thus, the last quarter is used as a “pushing” volume to prevent the return loss of a drug through exhalation.

The aim of the present study was to explore the differences in the pharmacokinetics of morphine using these two different pneumodosimetric nebulizations. The results of this study should help to make a rational choice of morphine inhalation technique for exploration in clinical studies.

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Methods 

Patients and Study Protocol 

The study was approved by the local Research Ethics Committee of Nicolas Copernicus University in Bydgoszcz, Poland, and all subjects gave written informed consent. The study involved cancer patients with a Karnofsky performance score higher than 70, admitted to the Oncology Centre in Bydgoszcz for diagnosis or management of their disease. None of the patients was taking opioids to control pain or breathlessness. On the first day, the patients were asked to perform six minutes of walking and the reading numbers test,²¹ after which they inhaled 100 μg salbutamol (or 200μg if necessary) to exclude a reversible bronchial obstruction. A spirometric evaluation was carried out before and then five, 20, and 60 minutes after the administration of salbutamol. The inhalation with saline was carried out by one of the two nebulization methods to which the patients were randomly assigned. Spirometric evaluation was performed before and then 5, 30, and 60minutes after the inhalation of saline. On the second day of the study, again after six minutes of walking and then reading numbers, patients received 5 mg of morphine by the same nebulization method as used previously with saline. In addition to the monitoring of spirometric parameters, venous blood samples were drawn before and then 30, 60, and 120 minutes after morphine administration to determine blood gas tension. Frequent blood samples were taken for determination of plasma morphine and the levels of morphine metabolites. Urine was collected over 24 hours in small quantities.

Equipment and Inhalation Systems 

The study was performed according to the standards for the nebulization of drugs prepared by the European Community Respiratory Health Survey.²² Irrespective of the chosen method, the integrated system for BCTS nebulization always consisted of a source of compressed air from the collection point (AGA Instal, Rzeszow, Poland), regulated by a flow meter (Farum, Warszawa, Poland) provided with a standard joint (AGA Instal), and a compressed air tube of 1.8 m length (Intersurgical, Wokingham, UK) adapted to the pneumodosimeter PNEUMONEB^® (abcMED, Krakow, Poland).²⁰

In the BCTS-S and BCTS-MC methods, aerosol was generated by nonventilated MC (Intersurgical) or ventilated Sidestream (MedicAid, Pagham, UK) nebulizers. The MC nebulizer was adapted to the BCTS head (abcMED) by M22 tubes (Intersurgical). In the BCTS-S method, the Sidestream nebulizer was connected to the BCTS head in a way that enabled the additional air stream collected from the outside to flow through the device reservoir at a velocity of 14L/minute. In the BCTS-S method, the total air flow was equal to 22L/minute (8L/minute of compressed air and 14L/minute of ambient air from the chamber). A pneumotachograph dPP^® (abcMed) served not only as a mouthpiece but also as a part of the system that constantly measured air flow and volume during inhalation by connection with the pneumodosimeter.

Inhalation Procedure 

Morphine HCl solution (20mg of substance in 1 mL saline) was prepared under sterile conditions by the local pharmacy. The inhalation was programmed to deliver 5 mg morphine at the mouthpiece based on the output rate, the calculation of which was made each time (by weighing) just before and after nebulization.

On the first day of the study, the patients were trained in how to breathe effectively for the nebulization method randomly chosen that day. Patients were seated in an upright position at rest, fitted with a nose clip, and inhaled aerosol through a mouthpiece under otherwise normal breathing conditions. In the BCTS-S or BCTS-MC method, the pattern of inhalation was controlled by the circuit, composed of the nebulizer, pneumotachograph, and pneumodosimeter and displayed as a real-time pattern on a computer screen. In the BCTS-S method, morphine was given only to the third quarter (50%–75%) of inspired air, whereas in the BCTS-MC method, to the first phase (0%–25%) of inspiration. The patients could see when the aerosol pulses were administered and whether their inspiration was deep and fast enough to evoke the injection of the morphine bolus. Delivery of the medication bolus occurred only if the flow rate was higher than 200mL/second and the previous exhaled volume greater than 25% of volume capacity. The device stopped automatically when a 5 mg morphine dose was delivered.

Analytical Procedures 

This method has been described in detail by Bogusz et al.²³ Two milliliters of whole blood buffered to pH 8.5–9 with 1 M NaOH was extracted with 6mL of chloroform and isopropyl alcohol (9:1) in an ultrasonic bath for two hours. For the extractions from urine, 25 mL amounts were used together with 75mL of the mixture as earlier. The organic phases were separated and vaporized until dry. The dried remainder was dissolved in methanol and analyzed with liquid chromatography (LC)/mass spectrometry. The analysis was carried out by LC with a mass detector using a chromatography set (Agilent Technologies 1100 Series, Agilent Technologies, Waldbronn, Germany) consisting of a liquid chromatograph equipped with a gradient pump, autosampler, and mass detector. For the analysis, the Ecocard cartridge (125 × 3mm) Superspher Select B (Merck, Darmstadt, Germany) was used. Mobile phase 50 mM ammonium formate (pH=3.0):acetonitril (90:10v/v), with flow rate of 0.6mL/minute, is used for the determination of morphine-3-glucuronide (M3) and morphine-6-glucuronide (M6). Mobile phase 50 mM ammonium formate (pH=3.0):acetonitril (95:5v/v), with flow rate of 0.6mL/minute, is used for the determination of morphine. Detection was performed using the single ion mode—for morphine, molecular ion=286, and for M3 and M6, molecular ion=462.

Statistical analysis of spirometric, gasometric, and inhalation parameters was carried out using a licensed version of statistical software STATISTICA PL 5.0 for Windows (StatSoft Polska, Krakow, Poland). Pharmacokinetic analysis was conducted by fitting a two-compartment model, using the nonlinear least number of squares method or the Bayesian adaptive control.

The area under the curve (AUC), clearance (Cl), distribution volume (V_d), and the rate constants for elimination (k_1-0) and intercompartmental constants (k_1-2, k_2-1) were calculated using the computer program MW/Pharm Version 3.5 (Mediware, Zuidhorn, The Netherlands).²⁴ The 95% confidence intervals (CI) for the differences of group means were calculated wherever possible. To test the normal distribution, the tests were repeated using the medians of the groups.

As the zero hypothesis on the normal distribution of gasometric, spirometric, and inhalation parameters could not be excluded, the parametric analysis of variance (ANOVA), Tukey's post hoc test, and Student's t-tests were performed for analysis. The distribution of demographic parameters was not normal and, therefore, median rather than mean values were used.

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Results 

Ten patients were included in the study: five in the BCTS-S group and five in the BCTS-MC group. The patients' characteristics and demographics are presented in Table 1. The comparison of BCTS-S and BCTS-MC methods is presented in Table 2. Inhalation by the BCTS-S method lasted significantly shorter (6.6±2 minutes) compared with the BCTS-MC method (mean=28.8±9 minutes), and the number of breaths with morphine administration was clearly lower in the BCTS-S method (mean=100) than in the BCTS-MC method (mean=398). Correspondingly, the mean duration of morphine deposition in the respiratory system was shorter in the BCTS-S method than in the BCTS-MC method (1046 vs. 2666 milliseconds).

Table 1. Patient Characteristics and Demographics

FVCin=forced inspiratory vital capacity.

Patients 1–5 were assigned to BCTS-S and 6–10 to BCTS-MC.

Table 2. Comparison of Parameters of 5 mg Morphine Inhalation by the BCTS-S and BCTS-MC Methods (Student's t-test)

SD=standard deviation.

Adverse Effects 

The most frequent adverse effect of nebulized morphine was dryness in the mouth (Patients no. 2 and 10). Two patients complained of the bitter taste (Patients no. 1 and 2). In one patient (no. 5), transient hypotension (70/40mm Hg) with sweating was observed 30 minutes after termination of morphine inhalation. The patient recovered after 15 minutes.

Pharmacokinetics 

The summary of pharmacokinetic data is presented in Table 3. In general, the BCTS-S method of administration produced an AUC value 2.6 times higher for morphine, 8.3 times higher for M6, and nearly seven times higher for M3 compared with the BCTS-MC method. These differences were statistically significant (P<0.05). In the BCTS-S method, relatively more metabolites were produced than with the BCTS-MC method.

Table 3. Pharmacokinetics of Morphine and Its Metabolites After Inhalation of 5 mg Morphine HCl Using Two Different Methods of Inhalation

C_max=maximum concentration; AVG=average; SD=standard deviation; AUC=area under the curve; Cl=clearance.

There were five patients in each of the BCTS-S and BCTS-MC groups. The CIs could not be calculated where the SDs were very much dissimilar in each group.

In the BCTS-S method, the mean M/M6 ratio was 0.13, and in the BCTS-MC method, it was 0.45. The difference of the means with 95% CI was 0.32 (0.09–0.55). The M3/M6 ratio in both the BCTS-S and BCTS-MC methods was approximately 1.0, suggesting that in most cases, comparable amounts of M3 and M6 were produced (Fig. 1a and c). The difference of the means with 95% CI was 0.08 (−0.77 to 0.93). Only in Patient 3 (BCTS-S group, see Fig. 1b), much more M3 was formed than M6 (M3/M6 ratio, 2,3). The median time to maximum plasma levels for M3 and M6 was shorter in the BCTS-S method, being 0.33 and 0.50 hours, respectively (20 and 30 minutes). The corresponding median times in the BCTS-MC method were 0.72 and 0.72 hours, respectively (43 minutes), but this was probably because of much slower morphine administration. The difference of the means and 95% CI for time to maximum concentration (T_max) for M3 was 0.26 (−0.01 to 0.51) and for M6, 0.17 (0.01 to 0.33). After the first peak in most patients treated with the BCTS-S but not the BCTS-MC method, there was a second peak for one or both metabolites at about two hours (Fig. 1).

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• Fig. 1 

  Plasma concentrations of morphine (♦), M3 (▴), and M6 (■) in two patients treated with the BCTS-S method (Patient 1 [a] and Patient 3 [b]) and one patient treated with the BCTS-MC method (Patient 10 [c]). Note in Patients A and B the second peak for the metabolites after about two hours.

Urine Excretion 

In most cases, two to three times more morphine was excreted than M3 and M6. On average, only 0.17% of the administered dose in the BCTS-S method and 0.14% in the BCTS-MC method were recovered in urine as morphine and metabolites (data not shown). Most of the excretion took place in the first 12 hours.

Spirometry 

Unrelated to the nebulization method, neither saline nor morphine significantly changed the forced expiratory volume in 1 second (FEV₁) and FEV₁/forced inspiratory vital capacity measured in the group of 10 patients (data not shown). However, there was a significant decrease of FEV₁ observed 20 minutes after salbutamol (100μg) administration compared with the values before and five minutes after salbutamol nebulization. The significance of this finding is uncertain. There was an important variability in the FEV₁ value measured on the second day (before morphine administration), which was significantly lower than that on the first day (before salbutamol and saline inhalation) of the study (ANOVA F(1, 14)=15.68; P<0.0002). When the activity was assessed, no significant difference was observed in the six minutes of walking between those days (data not shown).

Gasometry 

No significant impact of 5 mg morphine inhalation on pCO2, pO2, or saturation was observed up to 120 minutes for both groups compared with pretreatment values (data not shown).

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Discussion 

In the preparation for this study, we performed a morphine pharmacokinetics study using traditional pneumatic methods of morphine inhalation with six patients (data not shown). In these methods, morphine is nebulized continuously during inspiration and expiration. The results showed a large variation in pharmacokinetic results, probably because of significant and unpredictable losses in the exhaled air, adsorption to the mouth mucous membranes, and unquantifiable losses through the equipment. All the methods implemented in clinical trials reviewed by Jennings et al.¹ used these methods of traditional pneumatic inhalation; hence, it is not surprising that the results are variable and difficult to interpret. In addition, these studies were conducted without knowing exactly where the morphine should be deposited, because there was no clear idea exactly where the opioid receptors, possibly involved in breathlessness, were localized.

The two methods used in this study were largely free of these disadvantages. Any variability of results in this study was caused by patient condition and method of inhalation, rather than the equipment, which resembles clinical circumstances more closely. The presence of inflammatory disease, including cancer of the lung (but also in other tissues), may change the availability of opioid receptors for drug binding. Hence, the data obtained with healthy volunteers may be relevant for the central effect of morphine on pain but not relevant to the peripheral phenomena. The opioid receptors in the peripheral tissues need to be activated before binding of the drug. It was demonstrated that enhanced local inflammation results in a higher density of opioid receptors and improved topical opioid efficacy.²⁵, ²⁶, ²⁷

The inhalation of nebulized morphine using two different pneumodosimetric methods did not cause significant adverse effects in the patient population studied. The patients selected for this study were not breathless at rest and the effect on breathlessness was not assessed in this study. Neither morphine nor saline had significant effects on the spirometric parameters in this population. In the past, morphine was dreaded by physicians for its ability to free histamine from mast cells and induce bronchial constriction.²⁸, ²⁹, ³⁰ In clinical practice, nebulized morphine does not cause this effect in volunteers,³¹ and we can confirm that none of our patients experienced bronchial constriction after the inhalation of nebulized morphine. However, for ethical reasons, inhalation of morphine in our study was not tested on patients with significant bronchial constriction.

A review of the pharmacokinetic data obtained in this study revealed significant differences between the two methods tested. In general, the AUCs obtained after morphine inhalation with both the BCTS-S and BCTS-MC methods were lower than those obtained in the acute study with morphine inhaled through the AERx system (Aradigm Corporation, Hayward, California, USA).³¹ In the latter, morphine is injected early into the inspired air as homogeneous small particles (1–2μm) in a single breath, and its administration is repeated every minute.³², ³³ This method of application is intended to produce a rapid rise in plasma levels of morphine to control breakthrough pain. The bioavailability of morphine in the AERx study was measured as 59% compared with that in the intravenous (IV) administration of the same dose. Our methods of inhalation are probably much less efficient in producing a rapid increase in plasma levels of morphine and are, thus, worthless when a systemic effect is needed. On the other hand, when these methods are tested on breathless patients, the effect will rather be local but not systemic. Drug deposition in bronchi and alveoli mostly depends on the aerosol particle size. This is evidenced by Usmani et al.,³⁴, ³⁵ who showed that regional targeting of the beta-2 agonist to the trachea-bronchial tree resulted in improved drug effectiveness, assessed as the reverse of bronchoconstriction.³⁵

The BCTS-S method was designed to deposit morphine in the trachea and bronchi and not to cause rapid absorption in the alveoli. In this method, the fast inhalation of larger particles (2–5μm), which are deposited mainly in the trachea and bronchi, resulted in significantly higher AUCs for morphine. However, what is more interesting is that more M6 was produced from the same dose of morphine (M/M6 ratio, 0.10). This ratio in the literature has been reported as being between 0.18 and 0.85 using different methods of morphine administration.³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰ What is more important is that the M3/M6 ratio was approximately 1.0. The reported M3/M6 ratios are usually between 3.3 and 9,³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³ independent of the route of administration. In our study, there were no differences in the M3/M6 ratio between the BCTS-S and the BCTS-MC methods (Table 4).

Table 4. M/M6 and M3/M6 Ratios and Individual T_max for M3 and M6 in Two Different Methods of Morphine Inhalation

AVG=average; SD=standard deviation.

The T_max for morphine metabolites in the BCTS-S method was 20–30 minutes. This was a significantly shorter time than that in the BCTS-MC method. This is also much shorter than reported after intranasal morphine administration, where T_max was around two hours.³⁹ In our study, patients showing higher plasma levels (BCTS-S) also showed a second peak for metabolites, which appeared two hours after the start of the administration. This may suggest that the metabolites are formed in the usual way in the liver. Altogether, this means that, especially with the BCTS-S method, morphine is rapidly metabolized to the metabolites probably already in the lung tissue and, as a result of this, more M6 is produced from each molecule of morphine. This is significant, as M6 is thought to be important in the treatment of breathlessness.⁴⁴, ⁴⁵

Different glucuronidases are involved in the synthesis of M3 (UGT 1A1, 1A3, 1A6, 1A8, 1A9, 1A10, and 2B7), but only 2B7 is able to catalyze glucuronidation both to M3 and M6.⁴⁶ In fact, the ratio of metabolites (M3/M6) after systemic administration is usually more than 3. This suggests that many glucuronidases other than those listed earlier, which are only able to produce M3, are involved. The lung is an important organ that first comes into contact with airborne toxins and carcinogens and contributes to their neutralization. Although earlier studies did not reveal the expression of UGT2B7 in the lung,⁴⁷, ⁴⁸ a recent study by Ren et al.⁴⁹ confirmed the presence of small amounts of UGT2B7 in the lung and the absence of UGT1A9, normally involved in glucuronidation to M3. This kind of balance shift can explain why, locally, lung tissue may have produced almost equal amounts of both metabolites in all but one of our patients. An alternative explanation for this phenomenon could be that UGT 2B7 produces M6 preferentially at lower concentrations of morphine. This was noticed when brain slices were incubated with morphine.⁵⁰

As the T_max for metabolites was much shorter than previously reported,³⁹, ⁴¹, ⁴³ it is possible that inhaled morphine is metabolized in the bronchial epithelium. The second peak at two hours suggests that glucuronides produced in the liver can also be measured later in the plasma.

Our study has several limitations. The number of patients is small, and the results cannot be generalized to cancer patients who are breathless. The two methods of inhalation do administer the same dose of morphine but within a different time. Because the particles were so small, it took much longer (28.8 minutes on average) to nebulize the drug in the BCTS-MC method. This means that the Cl of the drug from systemic circulation was only slightly higher than the absorption. In the BCTS-S method, the drug is deposited in larger particles, and the dose application each time is much greater than the Cl; hence, the measurable plasma concentrations are higher.

The aim of the study was to compare two inhalation methods. However, we did not compare the plasma curves obtained with the IV administration of the same dose; hence, we cannot calculate the bioavailability. This was because cancer patients could not be sampled as much as the volunteers. Dershwitz et al.³³ reported the total bioavailability of 59% of inhaled morphine, but their method of administration was designed to have fast delivery of high morphine plasma concentrations to control breakthrough pain. Our study was designed to have a maximum local effect in the bronchial tree and a minimum of systemic effect. However, we cannot say what happened to the inhaled morphine. Morphine administered by both methods most probably remained mixed within the bronchial mucus and was never absorbed systemically. The low urine recovery of morphine and its metabolites supports this notion. To our knowledge, there are no articles reporting on urinary morphine excretion in cancer patients; hence, we cannot compare these results with those from any other study.

The study by our group concerning opioid receptor localization in the lung shows a high concentration of receptors superficially in the bronchial wall¹⁸ (Krajnik et al., in press, 2009). These receptors are related to the C-sensory fibers and bronchial epithelium, and in our hypothesis, are responsible for reducing breathlessness. This hypothesis is supported by the studies with isolated bronchial epithelium. In these studies, administration of morphine inhibits the release of proinflammatory neuropeptides from sensory nerve terminals within lung tissue, decreasing neurogenic inflammation effects,⁶, ⁷, ⁸ which may be important in the treatment of breathlessness.

In conclusion, this study reveals the unique pharmacokinetics of inhaled morphine and suggests that this drug is metabolized locally by glucuronidase in the lung. Increased relative concentrations of M6 may be the key in understanding the effect of inhaled morphine on breathlessness. Although there are still many questions to be answered, it is possible that targeting the deposition of morphine in the bronchial epithelium rather than the alveoli may change its absorption and metabolism. If these findings are confirmed, they may form an important stimulus for revisiting the idea of morphine inhalation for the palliation of breathlessness in terminally ill patients. Once more we have shown that conducting even well-designed controlled studies is worthless when the study lacks internal validity, the target of the treatment is unknown, and when the methods of drug administration are not well chosen. This also may explain why morphine inhalation may be found to be effective in a few selected cases (as only these are reported) but not in controlled studies.

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