Respiratory Medicine 207 (2023) 107119

Contents lists available at ScienceDirect

Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

A narrative review on pain control interventions for non-surgical

pleural procedures
Ann Du a, Liam Hannan a, b, Sanjeevan Muruganandan a, b, *
a
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
b
Department of Respiratory Medicine, Northern Health, Epping, Victoria, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: Pleural diseases are common and frequently result in disabling symptoms, impaired health-related quality of life
Pleural procedure and hospitalisation. Both diagnosis and management often require pleural procedures and despite a variety of
Pain pain control strategies available for clinicians to employ, many procedures are still complicated by pain and
Analgesia
discomfort. This can interfere with procedure success and can limit patient satisfaction. This review examines the
Visual analogue scale (VAS)
evidence for pain control strategies for people undergoing non-surgical pleural procedures. A systematic liter­
ature search was undertaken to identify published studies examining different pain control strategies including
pharmacological (sedatives, paravertebral blocks, erector spinae blocks, intrapleural anaesthesia, epidural
anaesthesia, local anaesthetic, methoxyflurane, non-steroidal anti-inflammatory drugs [NSAIDs], opioids) and
non-pharmacological measures (transcutaneous electric nerve stimulation [TENS], cold application and changes
to the intervention or technique). Current literature is limited by heterogeneous study design, small participant
numbers and use of different endpoints.
Strategies that were more effective than placebo or standard care at improving pain included intrapleural local
anaesthesia, paravertebral blocks, NSAIDs, small-bore intercostal catheters (ICC), cold application and TENS.
Inhaled methoxyflurane, thoracic epidural anaesthesia and erector spinae blocks may also be useful approaches
but require further evaluation to determine their roles in routine non-surgical pleural procedures. Future
research should utilise reliable and repeatable study designs and reach consensus in endpoints to allow
comparability between findings and thus provide the evidence-base to achieve standardisation of pain man­
agement approaches.

1. Introduction anaesthetic [6,8,9]. Unfortunately, despite improvements in equipment

Pleural disease encompasses a range of disorders involving the
pleura or pleural cavity. These are typically limited to the collection of
fluid (effusion), pus (empyema), blood (haemothorax), and air (pneu­
mothorax), malignant infiltration of the pleura or pleural inflammation
(pleurisy). Pleural disease is common with an annual incidence esti­
mated at up to 360 per 100,000 population and its incidence continues
to increase [1]. It is often associated with significant impairment in
quality of life and increased morbidity and mortality [2–7].
Most people with pleural disease are symptomatic and frequently
require hospitalisation for diagnostic or therapeutic pleural procedures
(Table 1). Many of these can be performed under local anaesthesia and/
or conscious sedation, and these non-surgical procedures have the
advantage of avoiding the additional risks associated with a general
and techniques, non-surgical pleural procedures are still frequently
complicated by pain both during and after their performance [10,11].
Pain during non-surgical pleural procedures results primarily from
direct irritation of pain fibres innervating the skin, parietal pleura and
periosteum of the ribs. The parietal pleura in particular can be exqui­
sitely painful due to heavy innervation by somatic intercostal nerves and
the phrenic nerve [12]. Apart from direct irritation from the manipu­
lation of instruments [13,14], non-surgical pleural procedures
(including pleural biopsies, intrapleural fibrinolysis and chemical
pleurodesis) can also induce a painful local inflammatory reaction.
Intercostal or indwelling pleural catheters can cause pain
post-procedure that is exacerbated with coughing, movement or during
their removal [15,16]. Rapid or large volume pleural fluid drainage may
also produce pain that is attributable to pleural pressure swings.

* Corresponding author. Department of Respiratory Medicine, The Northern Hospital, 185 Cooper St, Epping, VIC, 3076, Australia.
E-mail address: Sanjeevan.muruganandan@nh.org.au (S. Muruganandan).

https://doi.org/10.1016/j.rmed.2023.107119
Received 7 July 2022; Received in revised form 5 January 2023; Accepted 11 January 2023
Available online 13 January 2023
0954-6111/© 2023 Elsevier Ltd. All rights reserved.
A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 1 influenced pain were also included. All considered studies required an
Frequency of pleural procedures performed in 72,240 individuals outcome that measured pain scores and/or reported patient experience.
during hospitalisations for MPE in the USA (2012) [77]. Non-surgical pleural procedures include medical thoracoscopy or pleu­
Procedure Frequency performed roscopy, ultrasound (US) guided pleural biopsy, chemical pleurodesis,
ICC insertion 31.9%
intercostal catheter (ICC) or indwelling pleural catheter (IPC) insertion
Thoracentesis 74.8% and removal, thoracocentesis and intrapleural fibrinolysis. Of the 1190
Chemical pleurodesis 14.2% studies identified, 31 studies were included for the final review (Fig. 1),
Via chest tube 57% which have been summarised in Table 3. Adverse events from the
Via thoracoscopy 43%
various analgesic interventions were also considered (Table 4).
Medical thoracoscopy 9.2%

1.1. Evaluating pain

Pain can negatively influence an individual’s perception of a pleural
procedure and their overall experience, thus influencing their willing­ Pain is subjective and, therefore, comparison across studies with
ness to undergo future procedures [17]. Excessive pain can also require different measurement approaches can be problematic. It is not feasible
additional rescue analgesia or result in prolonged periods of immobility, for studies evaluating pain control during pleural procedures to control
prolonging the length of hospital stay [18]. Post-procedure complica­ all the variables that form part of the subjective experience of pain. Most
tions including venous thromboembolism, atelectasis or hospital ac­ studies evaluating different analgesic approaches to non-surgical pleural
quired infections may also be impacted by pain due to an inability to procedures considered and attempted to control for procedural factors
breathe deeply, cough or mobilise [19]. Effective pain control is there­ such as operator experience, technical proficiency, size and type of
fore essential both during and following non-surgical pleural equipment, patient positioning and the specific nature of the procedure
procedures. undertaken (drainage, pleural biopsy, adhesiolysis, pleurodesis)
This narrative review aimed to examine current approaches to pain [20–24]. However, very few studies attempted to account for patient
control for non-surgical pleural procedures and determine the evidence factors such as pre-procedure anxiety, previous experience of pleural
supporting their use. A literature search was performed using Medline procedures, pain tolerance and underlying disease severity. While these
Ovid, PubMed and Embase databases to identify studies published be­ are incredibly difficult factors to control for, they could be material to
tween January 1946 and December 2022 that evaluated methods of pain the success or failure of the employed pain control strategies, and this
control in adults with pleural disease undergoing non-surgical pleural represents a significant limitation of the literature in this area.
procedures. Search terms (Table 2) relating to analgesic approaches Visual analogue scale (VAS) or numeric rating scale (NRS) are the
were combined with terms relating to pain outcome measures and primary outcome measure used in most studies. While a valid approach,
procedure-specific terms. Studies were included if they involved adult these scales may not always be anchored using similar terms or may use
patients aged 18 years or older with pleural disease undergoing a non- similar terms that may be interpreted differently by patients [25]. Two
surgical pleural procedure. Studies that assessed an intervention that studies [26,27] determined that a 13 mm difference on VAS was the
minimum clinically important difference (MCID) after an intervention in
a cohort of emergency trauma patients. A more recent retrospective
Table 2 study [28] analysed two thoracocentesis trials and expanded upon this
Key search terms. by correlating 100 mm VAS scores against a 7-point Likert scale. Across
Key search terms Analgesia Pain Pleural 263 thoracocenteses, a ‘small, but significant increase in discomfort’ was
procedures associated with a mean VAS score of 16.04 mm (95% CI 6.86 to 25.21),
Synonyms and Analgesi* Pain Pleural
thus defining the MCID for chest discomfort using VAS as 16 mm. This
related terms Pain relief Procedural pain procedure* may be applied to interventions that are procedurally similar to thor­
Pain management Pain level Pleural acocentesis. However, due to the small sample size and the varying
Pain control Pain intensity intervention* mechanisms of pain with different pleural procedures, it is unclear
An?esthe* Pain score Medical
whether this MCID can be generalised to other pleural procedures.
Opi* Patient-reported thoracoscop*
NSAID outcome* Pleuroscop* A common surrogate endpoint chosen across studies of pain control
Non-steroidal anti- Patient Pleural biops* is the requirement for breakthrough analgesia. Standardised protocols
inflammator* outcome* Pleural aspirat* ensure breakthrough pain is managed similarly but can potentially
Thoracocentesis negate the utility of analgesic volume as an endpoint. Non-standardised
Thoracentesis
Intercostal
approaches may mean that management is heterogeneous, even if the
catheter degree of breakthrough pain is similar. Evidently there is an ongoing
Intercostal drain clinical and research need to accurately assess pain related to pleural
Chest tube procedures and to design robust comparison studies.
Chest drain
Pleurodesis
Sclerosant 2. Analgesic intervention for pleural procedures
Poudrage
Slurry 2.1. Intercostal catheter insertion and removal
Intrapleural
fibrinolysis
Query string (analges* OR “pain relief” OR “pain management” OR “pain
An ICC is a small hollow plastic tube inserted into the pleural space
control” OR an?esthe* OR opi* OR NSAID OR “non-steroidal that is connected to an underwater seal drain or a Heimlich valve, in
anti-inflammator*") AND (pain OR “procedural pain” OR “pain order to treat a pleural effusion, pneumothorax, haemothorax, empyema
level” OR “pain intensity” OR “pain score” OR “patient reported or following a surgical procedure [9]. There are various types of ICCs,
outcome*" OR “patient outcome*") AND (“pleural procedure*"
typically classified according to size (ranging from 8 to 36 French) and
OR “pleural intervention*" OR “medical thoracoscop*" OR
pleuroscop* OR “pleural biops*" OR “pleural aspirat*" OR insertion method. Small-bore ICCs are typically inserted with a
thoracocentesis OR thoracentesis OR “intercostal catheter” OR catheter-over-wire (Seldinger) approach, where a small incision is made,
“intercostal drain” OR “chest tube” OR “chest drain” OR and a guide wire is inserted into the pleural space through an introducer
pleurodesis OR sclerosant OR poudrage OR slurry OR needle. The needle is then withdrawn, and dilators are threaded over the
“intrapleural fibrinolysis")
wire in a twisting motion. Large-bore ICCs require a blunt dissection

2
A. Du et al.
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the included studies.
technique where intercostal tissues are dissected, in order to provide
direct access to the pleural space and allow placement of the ICC.
ICC insertion techniques are heterogeneous and pain control strate­
gies used during the procedure also vary considerably. Pre-medication
with opioids or anxiolytics may enhance pain control but studies
investigating their analgesic efficacy in ICC insertion are limited [9].
Extrapolation of data from medical thoracoscopy [20] suggests that
paravertebral blocks with long-acting local anaesthetics would provide a
significant and prolonged analgesic effect, although this has been poorly
studied. Instead, local anaesthetic infiltration with 1% lidocaine (up to 3
mg/kg) with or without adrenaline 1:100,000 into the ICC insertion site
is most commonly utilised [9]. The short duration of local anaesthetic
action or incomplete analgesia can result in the need for additional
administration midway during the procedure, which can be problematic
[29]. Topical lidocaine-prilocaine cream at the site of thoracocentesis
prior to the procedure was not more effective at reducing pain compared
to conventional infiltrative lidocaine (mean (±SD), 3.25 (±1.09) vs. 3.5
(±0.53) respectively, p = 0.517), however, it is a reasonable and safe
alternative [30]. Very few adjuncts to local anaesthetic infiltration have
been investigated with inhaled methoxyflurane prior and during the
procedure representing a potentially promising option [31]. This
inhaled volatile anaesthetic agent is easy to administer and has a fast
onset of action with good patient tolerability and satisfaction [32].
Further studies are required to make more conclusive statements on its
utility in pleural procedures.
Post-insertion, pain control strategies for those with ICCs are var­
iably employed and are often based on physician preferences. No
guidelines exist but anecdotally, opioids may be used if non-opioid an­
algesics provide insufficient pain control [33]. Alternatives to this
approach include intrapleural bupivacaine delivered via the ICC which
has been shown to be superior to placebo (normal saline) in individuals
3
Respiratory Medicine 207 (2023) 107119
with pneumothorax [23,34]. Administration of 20 ml of 0.5% bupiva­
caine with adrenaline every 8 h was associated with lower pain scores
(using VAS) within 5 min of administration and provided up to 4-h of
analgesia with each dose [23]. Pain control with bupivacaine may be
further optimised with co-administration of either intrapleural
morphine or intrapleural dexmedetomidine [35]. These agents were
associated with reduced pain scores, longer time to rescue analgesia and
some apparent improvements in respiratory parameters when compared
to either bupivacaine alone or placebo in a randomised controlled trial
[35]. Limited case series have also reported efficacy with the use of
epidural analgesia for ICC insertion and removal [36,37], however there
are questions around the feasibility of such an approach given the
expertise required for epidural placement.
In addition to the choice of pharmacotherapy for pain control during
ICC insertion, procedural techniques do appear to influence pain. The
use of smaller ICCs (<12F) and a Seldinger insertion technique has been
associated with significantly less pain than larger ICCs (>20F) and a
blunt dissection insertion technique [38–40]. Regardless of insertion
technique, once larger ICCs are in place, they are associated with
increased pain [38], again supporting moderation in the choice of ICC
size. The same observation appears to be true for ICC removal, with large
bore ICCs being significantly more painful to remove than pigtail cath­
eters [40]. For removal, non-pharmacological approaches have
demonstrated some apparent benefit with cold application around the
ICC site found to be superior to standard care [41,42], with ice packs
causing a quicker drop in skin temperature (to the level that produces an
analgesic effect) than gel pads [42].
One study using a pre-post design evaluated a multi-modal approach
of changes to staff education, pre-medication (using intravenous
morphine), local anaesthetic dosing (using a maximum safe dose based
on body weight) and improvements in ICC insertion technique. The
A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 3
Summary of evidence.
Author Study design Patient sample Pleural procedure Intervention(s) and/or Pain measure(s) Outcomes
(s) Comparison

ICC insertion and removal

Engdahl et al. (23) RCT (double Primary spontaneous ICC (20F) in situ 1. 8 hourly boluses of 20 ml Patient-rated pain with Mean VAS of the
blinded) pneumothorax (n = 0.5% interpleural VAS (0–100 mm) bupivacaine group was
22) bupivacaine with before all injections, 5, significantly than the
adrenaline, starting 4 h 15, 30, 60, 250 and placebo group after the
after ICC insertion and 480 min after the first first injection at 5, 15, 30
continued for 10 injections and second injections, and 60 min, after the
2. Normal saline (placebo) and 30 min after the second injection at 5 min
4th, 7th, 10th and after the seventh
injections injection at 30 min.
Additional analgesia No significant difference
requirements in additional analgesia
use between groups
Verma et al. (35) RCT (single blinded) Non-surgical patients ICC in situ 1. 2 mg/kg 0.25% Patient-rated pain with Median NRS was
in a cardio-thoracic intrapleural Bupivacaine NRS [1–10] recorded significant between
hospital, pleural only (B) before the intervention, groups at all time points
disease not specified 2. 2 mg/kg 0.25% then after the invention until block regression
(n = 28) Bupivacaine with 50 μg/kg at 30 min, 1hr, 3hr, 6 h, (15–18hr) except
Morphine (M) 9 h, 12 h, 15 h and 18 h between group M vs. D.
3. 2 mg/kg 0.25% Time to first analgesic Mean (±SD, CI) time
Bupivacaine with 0.5 μg/ demand (hours) to first analgesic
kg Dexmedetomidine (D) demand, significant
4. 0.8 ml/kg of normal between C vs. Ma, C vs. Da
saline (placebo) (C) and B vs. Da:
- D: 17.43 (±4.077, CI:
13.66–21.20)
- M: 15.57 (±4.504, CI:
11.41–19.74)
- B: 6.14 (±1.345, CI:
4.90–7.39)
- C: 1.43 (±0.535, CI:
0.93–1.92)
Rasihashemi et al. RCT (open-label) Spontaneous ICC insertion and 1. 14Fr pigtail catheter Patient-rated pain with Mean VAS in pigtail vs.
(40) pneumothorax (n = removal 2. 28Fr chest tube VAS (0-10) before, chest tube group:
42) during and after - Before: 4.95 vs. 4.9
insertion, and during - During: 7.52 vs. 8.14a
and after removal - 24 h after: 5.33 vs. 5.38
Additional analgesia - 48 h after: 3.76 vs. 4.29
requirements - Removal: 6.14 vs. 7.33a
Significantly less
analgesic use in pigtail vs.
chest tube groupa
Soydan et al. (42) RCT (open-label) Haemothorax, ICC removal 1. Cold application with Patient-rated pain with Mean NRS (±SD) in ice
pneumothorax, pleural two ice packs (each 15.5 × NRS (0-10) before, pack vs. gel pad vs.
effusion, hydatid cyst, 9cm) around chest tube during and 15 min after control:
pneumo-haemothorax, 2. Cold application with a removal - Before: 6.3 (±2.2) vs.
other pleural disease gel pad (15 cm radius) Additional analgesia 7.5 (±2.0) vs. 6.1 (±2.2)a
around chest tube (15 cm used - During: 5.0 (±2.6) vs.
radius) Time to first analgesic 6.4 (±3.4) vs. 7.1 (±2.4)a
3. No cold application demand - 15 min after: 1.9 ±(1.6)
(control) vs. 4.8 (±2.6) vs. 6.6
(±2.1)a
Significantly less
analgesia used in ice pack
vs. gel pad groupa and ice
pack vs. control groupa
Halili et al. (30) RCT (open-label) Pleural disease not Insertion of 1. 5 cc of 2% infiltrative Patient-rated pain with No significant difference
specified (n = 36) catheter for lidocaine (IL) NRS (0-10) in mean (±SD) pain
thoracocentesis 2. 2.5g of lidocaine- immediately after scores between IL vs. LPC
prilocaine cream around a procedure group: 3.5 (±0.53) vs.
20–25 cm2 area (LPC) 3.25 (±1.09)
Sabry et al. (39) RCT (open-label) Malignant pleural ICC insertion for 1. Small bore catheters Patient-rated pain with Mean VAS (±SD) in small
effusions (n = 60) drainage (10-12Fr) VAS (0–10 cm) during bore vs. large bore group
2. Large bore chest tubes insertion = 2.1 (±1.5) vs. 6.3
(28-32Fr) (±1.4)a
Ertuğ et al. (41) RCT (open-label) Pneumo-haemothorax ICC removal 1. Cold application with 5 Patient-rated pain with Mean VAS (±SD) of
(n = 61) pieces of 2 × 3cm ice cubes VAS (0–10 cm) before, intervention vs. control
Pleural effusion (n = in a waterproof bag, immediately after and group:
44) applied on an a 7 cm 5 min after removal - Immediately after: 3.85
Neoplasia, empyema, diameter area around entry (±1.75) vs. 5.6 (±1.94)a
pulmonary cysts (n = point of chest tube - 5 min: 1.13 (±0.95) vs.
35) 2. No cold application 1.51 (±1.10)a
(control)
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A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 3 (continued )
Author Study design Patient sample Pleural procedure Intervention(s) and/or Pain measure(s) Outcomes
(s) Comparison

Cottee et al. (31) Prospective single- Pleural disease not ICC insertion Methoxyflurane prior to Patient-rated pain and Mean (SEM) patient pain
arm interventional specified (n = 22) IPC insertion and during procedure (in anxiety with NRS (0- during procedure: 2.9
study Medical addition to conventional 10) during and after (0.5)
thoracoscopy local anaesthetic) procedure Mean (SEM) patient pain
Additional analgesia after procedure: 1.7 (0.5)
requirements Mean (SEM) patient
anxiety = 4.5 (0.6)
No patients required
further opiate analgesia
Luketich et al. (43) Prospective case Symptomatic ICC insertion 1. Revised protocol: staff Patient-rated pain and Mean pain (±SD) of
series malignant pleural training, patient anxiety with NRS revised protocol group vs.
effusions (n = 52) education, essential [1–10] during control group: 3.7 (±5.6)
premedication, max dose procedure vs. 6.2 (±0.76)a
of LA injection, proper Mean anxiety (±SD) of
delivery of LA, additional revised protocol group vs.
analgesia as needed control group: 1.5
2. Conventional protocol (±0.54) vs. 4.5 (±0.72)a
(control)
Rahman et al. (38) Retrospective cohort Pleural infection (n = ICC insertion, in Chest tubes sizes: <10Fr, Patient-rated pain Median [IQR] pain scores
study 128) situ and removal 10-14Fr, 15-20Fr and 20Fr using 4-point were higher in larger
categorical scale ICCsa:
immediately after - <10F: 6 [4–7]
insertion, while tube - 10–14F: 5 [4–6]
was in situ and after - 15–20F: 6 [5–7]
removal, summated to - >20F: 6 [6–8]
produce an overall pain 54% with an ICC >15F
score experienced moderate/
severe pain, compared to
27% with a <15F ICCa
No significant difference
in pain during removal
Holmes et al. (36) Case report 35 year-old woman at ICC (large bore) Thoracic epidural Anecdotal report Near total relief of
35 weeks pregnant in situ anaesthesia at T6-7 with excruciating pain
with recurrent basal infusion of 0.1% (uncontrolled by IV
spontaneous bupivacaine with 2 μg/mL opioids) was rapidly
pneumothorax fentanyl at 8 ml/h achieved
Bolus doses of 2 ml up to
every 10 min
Kempen et al. (37) Case report 22 year-old male with Chemical Thoracic epidural Anecdotal report Mitigation of severe pain
recurrent right pleurodesis with anaesthesia at T4-5 of after pleurodesis
spontaneous doxycycline 0.125% bupivacaine Painless removal of ICC
pneumothorax ICC removal containing 2 μg/mL of and epidural catheter the
fentanyl (rate = 6 cc/hr) next morning
before pleurodesis
Additional 12 mL of 0.25%
bupivacaine injected
75min
Infusion rate increased to
12 cc/hour
Pleural drainage
Senitko et al. (45) RCT (open-label) Pleural effusion (n = US guided 1. Continuous suction with Patient-rated pain with Mean change in pain
100) unilateral a vacuum bottle or wall NRS (0-10) before and score (±SD) of vacuum vs
thoracocentesis system during procedure manual drainage group:
2. Manual drainage via a 1.43 (±2.7) vs. 0.53
syringe (±1.7)a
Chemical pleurodesis
Sherman et al. (54) RCT (single- Malignant pleural Chemical 1. Group one: 200 mg 1% Patient-rated pain with Mean NRS (±SD) of
blinded) effusion (n = 18) pleurodesis with intrapleural lidocaine NRS [1–5] after group two vs. one: 1.7
Spontaneous tetracycline 2. Group two: 250 mg 1% procedure (±1.2) vs. 3.0 (±0.9)a
pneumothorax (n = 2) intrapleural lidocaine % patients free of pain
Both groups premedicated after pleurodesis in group
with 50 mg IM meperidine two vs. one: 70% vs.
10%a
Rahman et al. (22) RCT (open-label) Symptomatic Chemical Thoracoscopic pleurodesis Patient-rated pain with Mean VAS (±SD) of 12F
malignant pleural pleurodesis with (n = 206): VAS (0–100 mm) 4 vs. 24F chest tube group:
effusion (n = 320) talc 1. NSAID: oral ibuprofen times daily after 22.0 (±16.6) vs. 26.8
800 mg 3 times daily procedure (for up to 5 (±16.9)a
2. Opioid: oral morphine days) Mean VAS (±SD) of
10 mg 4 times daily Additional analgesia NSAID vs. opiate group:
Non-thoracoscopic requirements 22.1 (±16.9) vs. 23.8
pleurodesis (n = 114): (±15.8)
1. 12F chest tube and % requiring rescue
NSAID analgesia in NSAID vs.
2. 12F chest tube and opiate group: 38.1% vs.
opioid 26.3%a
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A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 3 (continued )
Author Study design Patient sample Pleural procedure Intervention(s) and/or Pain measure(s) Outcomes
(s) Comparison

2. 24F chest tube and

NSAID
4. 24F chest tube and
opioid
Chandra et al. (59) RCT (open-label) Pneumothorax (n = Chemical 1. TENS (80 Hz) with two
60) pleurodesis with electrodes placed on either
doxycycline side of chest tube for 45
min after procedure (as an
adjunct to IV infusion of
75 mg of diclofenac
sodium)
2. Identical electrodes with
no current (placebo), in
addition to the same
NSAID therapy
Clementsen et al. RCT (open-label) Malignant pleural Chemical 1. Small percutaneous
(58) effusion (n = 18) pleurodesis with catheter (10F) – inserted at
tetracycline bedside
2. Conventional large-bore
chest tube (24F) – inserted
during thoracoscopy
(±drainage, biopsy)
100 mg bupivacaine
instilled with tetracycline
Both groups premedicated
with oral diazepam
Keeratichananont Prospective study Symptomatic Chemical 1. 100 mL of autologous
et al.(52) malignant pleural pleurodesis with venous blood (AB)
effusion (n = 110) 8-10Fr or 20-32Fr followed by 50 mL of
ICC normal saline
2. 4g of sterile talc
suspended in 100 mL of
normal saline
Keeratichananont Prospective study Symptomatic Chemical 1. 100 mL of autologous
et al. (53) malignant pleural pleurodesis with venous blood (AB)
effusion (n = 48) 8-10Fr or 20-32Fr followed by 50 mL of
ICC normal saline (ABP group)
2. 1g of tetracycline
diluted in 100 mL of
normal saline
Lee et al. (24) Prospective single- COPD patients with Thoracoscopic 250 mg 1% intrapleural
arm interventional pneumothorax (n = 5) pleurodesis (10 lidocaine administered
study mm over parietal pleural
thoracoscope) surface via spray catheter
with talc Premedicated with IM
pethidine and IV
midazolam
Oral tramadol 50 mg was
administered 3 h after the
procedure, then every 8-
hourly
Kempen et al. (37) Case report 22 year-old male with Chemical Thoracic epidural
recurrent right pleurodesis with anaesthesia at T4-5 of
spontaneous doxycycline 0.125% bupivacaine
pneumothorax ICC removal containing 2 μg/mL of
fentanyl (rate: 6 cc/hr)
before pleurodesis
Additional 12 mL of 0.25%
Patient rated pain with Mean VAS (±SD) of TENS
VAS (0–10 cm) before, vs. placebo group at:
immediately after, 2, 4, - Immediately after: 0.26
6 and 8 h after (±0.44) vs. 0.50 (±0.57)
procedure - 2 h: 0.56 (±0.50) vs.
NSAID requirements 0.60 (±0.67)
- 4 h: 0.63 (±0.66) vs.
1.43 (±0.62)a
- 6 h: 0.83 (±0.69) vs.
1.56 (±0.62)a
- 8 h: 0.96 (±0.85) vs.
1.86 (±0.63)a
Total dose in mg (±SD) of
diclofenac used in TENS
vs. placebo group: 80.0
(±15.25) vs. 93.33
(±24.50)a
Patient discomfort No significance
evaluated with difference in discomfort
questionnaire during between groups during
and after procedure the instillation of
tetracycline
9/9 participants found
the presence of the 24F
‘very or somewhat
unpleasant’ vs. 2/9
treated with the 10F ICCa
Patient-rated pain on Mean (±SD) NRS of AB
NRS (0-10) 5 min vs. talc group at:
before, then 5 min, 6 h - 5 min after: 1.7 (±1.5)
and 24 h after vs. 5.4 (±3.0)a
Additional analgesia - 6 h: 0.9 (±1.3) vs. 3.5
requirements (±3.3)a
- 24 h: 0.5 (±1.0) vs. 2.3
(±2.9)a
% of participants
requiring additional IV
opioid in AB vs. talc
group: 9% vs. 26%a
Patient-rated pain on Mean (±SD) NRS of AB
NRS (0-10) 5 min vs. tetracycline group at:
before, then 5 min, 6 h - 5 min after: 1.7 (±1.5)
and 24 h after vs. 5.4 (±3.0)a
Additional analgesia - 6 h: 0.9 (±1.3) vs. 3.5
requirements (±3.3)a
- 24 h: 0.5 (±1.0) vs. 2.3
(±2.9)a
% of participants
requiring additional IV
analgesia in AB vs.
tetracycline group: 4.2%
vs. 75%a
Patient-rated pain with Median VAS immediately
VAS (0–10 cm) after procedure: 3
immediately after Median 8 hourly VAS day
procedure and every 8 1–2 post op: 2
h
Anecdotal report Mitigation of severe pain
after pleurodesis
Painless removal of ICC
and epidural catheter the
next morning
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A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 3 (continued )
Author Study design Patient sample Pleural procedure Intervention(s) and/or Pain measure(s) Outcomes
(s) Comparison

bupivacaine injected
75min
Infusion rate increased to
12 cc/hour
Medical thoracoscopy
Abdelhady et al. (69) RCT (double- Pleural effusion (n Medical thoracoscopy 1. Intrapleural lidocaine (3 Patient rated pain with Mean VAS (±SD) in
blinded) = 26) with rigid mg/kg) via 26F chest tube VAS (0–100 mm) lidocaine vs. placebo
thoracoscope under 2. Normal saline (placebo) before, during and 2 h group:
conscious sedation via 26F chest tube after - Before: 50 [4.3–60] vs.
(±pleurodesis) 27.5 [10–62.5]
- During: 49 (±33.2) vs.
57.4 (±27.6)
- 2 h after: 43.5 (±28.3)
vs. 42.5 (±33.7)
Sirohiya et al. (67) RCT (double- Pleural disease not Medical thoracoscopy 1, Sedation with Patient rated faces pain Mean pain rating (±SD)
blinded) specified (n = 60) with semi-rigid midazolam (M) 2 mg IV, scale (6 categories from of M vs. D group: 4.2
thoracoscope followed by 1 mg boluses ‘no pain to excruciating (±2.3) vs. 2.9 (±1.8)a
(M) pain’) after procedure Additional fentanyl dose
2, Dexmedetomidine (D) Additional analgesic used was significantly
IV infusion at 1 μg/kg, then (fentanyl) requirements greater in M vs. Da
at 0.2–0.87 μg/kg
All patients also received 1
μg/kg of fentanyl
Bansal et al. (62) RCT (single- Undiagnosed Thoracoscopic pleural 1. Mini thoracoscope with Patient-rated pain with Mean VAS (±SD) of MT
blinded) exudative pleural biopsy, under 5.5 mm external diameter VAS (0–100 mm) vs. SR group: 41.9
effusion (n = 73) conscious sedation and 3.5 mm working during procedure (±17.3) vs. 32.1 (±16.5)a
channel (MT) Midazolam and No significant difference
2. Semi-rigid thoracoscope fentanyl requirements in doses of midazolam
with 7 mm external and fentanyl required
diameter and 2.8 mm between groups
working channel (SR)
Abo-Zeid et al. (20) RCT (open- Exudative pleural Medical thoracoscopy 1. Unilateral 3-level (T3-5) Patient-rated pain with Median VAS [IQR] in LI
label) effusion (n = 63) with 11 mm paravertebral block (PVB) VAS (0–10 cm) group vs. 3 level PVB vs.
thoracoscope under with 9 ml 0.5% immediately after, 1, 6 2 level PVB groups:
conscious sedation bupivacaine and 4 ml 2% and 12 h after - Immediately after: 5
(±aspiration, mepivacaine procedure [2–7] vs. 1.5 [0.25–3] vs.
adhesiolysis, biopsy 2. Unilateral 2-level (T4-5) 2 [0–4.5]a
and 30F ICC PVB with 9 ml 0.5% - 1 h after: 4 [3–6] vs. 2
insertion) bupivacaine and 4 ml 2% [1.25–4] vs. 2 [1–3.5]a
mepivacaine
3. Local infiltration (LI)
with 4.5 ml 0.5%
bupivacaine and 2 ml 2%
mepivacaine
Grendelmeier et al. RCT (open- Suspected Medical thoracoscopy 1. Propofol 10 mg IV, Patient rated Median VAS [IQR] of
(21) label) malignancy, with 7 mm followed by continuous discomfort and anxiety propofol vs. midazolam
pleural effusion, thoracoscope (± infusion of propofol at with VAS (0–10 cm) group:
empyema, pleural biopsy, initial rate of 0.3 mg/kg/ after the procedure - Discomfort VAS: 1
pneumothorax (n adhesiolysis, min Additional analgesia [0.75–2.25] vs. 1 [0–3]
= 90) pleurodesis and ICC 2. Midazolam 2 mg IV, (pethidine) - Anxiety VAS: 2.5
insertion) followed by 1–2 mg IV requirements [0–4.25] vs. 3 [0–6]
boluses Mean (±SD) pethidine
Premedicated with 4 mg dose (mg) required for
hydrocodone propofol vs. midazolam
Additional 50 mg group: 45 ± 25 vs. 61 ±
pethidine given during 31a
thoracoscopy
Kostroglou et al. (66) Prospective Pleural effusion (n Medical thoracoscopy 1. Dexmedetomidine IV Patient-rated pain with Mean (95% CI) NRS pain
study = 55) (± talc pleurodesis) infusion, supplemented NRS (0-10) after scores of DEX + MZ/F vs.
with midazolam/fentanyl procedure MZ/F group: 1
(DEX + MZ/F) Additional analgesic (0.33–1.67) vs. 2.54
2. Conventional sedation requirements (1.5–3.6)a
with midazolam/fentanyl % requiring IV
(MZ/F) acetaminophen in DEX +
MZ/F vs. MZ/F group:
21% vs. 67%a
Reda et al. (68) Prospective Pleural disease not Medical thoracoscopy 1. Intrapleural anaesthesia Patient-rated pain with Median VAS [IQR] of CS
non-randomised specified, 90% had (IPA) with 1 mg/kg of 1% VAS (0–10 cm) after group vs. IPA group: 8
study malignant pleural lidocaine procedure [6.75–9] vs. 1 [0–3.75]a
disease (n = 20) 2. Conscious sedation (CS) Additional analgesia % requiring IV analgesia
with standard doses of IV requirements post-procedure in CS vs.
midazolam IPA group: 80% vs. 10%
Sharp et al. (72) Retrospective Pleural effusion (n Medical thoracoscopy Erector spinae plane block Patient-rated pain with No significant difference
case series = 23) using rigid with 0.5% ropivacaine (n NRS (0-10) before and between mean pre-
after procedure operative and post-
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A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 3 (continued )
Author Study design Patient sample Pleural procedure Intervention(s) and/or Pain measure(s) Outcomes
(s) Comparison

Pneumothorax (n thoracoscope under = 24) or 0.35% Additional analgesia operative pain scores (1.4
= 3) conscious sedation ropivacaine (n = 2) requirements ± 2.1 vs, 2.4 ± 2.9, p =
0.221)
Average intra-operative
and post-operative opioid
consumption (converted
to oral morphine
equivalents) was 18.4 ±
15.8 and 11.2 ± 19.6 mg
respectively
Pedoto et al. (73) Case report 55 year-old Medical thoracoscopy Midpoint transverse Anecdotal report Patient did not require
woman with under conscious process to pleural (MTP) additional analgesia for
recurrent sedation (±drainage, block at T6 with the duration of procedure
malignant pleural poudrage and IPC bupivacaine and lidocaine, and post-procedure for
effusion insertion) and adjunctive 16 h
dexamethasone and
clonidine
McPherson et al. (71) Prospective Pleural disease not Medical thoracoscopy Erector spinae plane blocks Patient-rated pain with Mean NRS (±SEM):
single-arm specified (n = 9) under conscious at T5-7 using 20–35 mL of NRS (0-10) before and - Before: 0.66 (±0.27)
interventional sedation 0.25% bupivacaine after procedure - After: 1.56 (±0.76)
study Additional analgesia - 3–12 h post discharge:
requirements 3.56 (±0.7)
- 24 h after: 5.56 (±0.9)
78% required oral
analgesia day 0 post
discharge and 55%
required analgesia day 1
post op
Agnoletti et al. (70) Prospective Pleural disease not Medical thoracoscopy Thoracic paravertebral Patient rated pain with 11.5% of patients had
single-arm specified (n = 26) under conscious block at T3-7 with 1% NRS (0-10) NRS>3
interventional sedation (±drainage, ropivacaine and 2% Additional analgesia Two patients had NRS>5
study biopsy, deloculation, lidocaine requirements two days after the
talc pleurodesis) procedure
One patient had NRS>6
day one post op
No additional analgesic
use for 24 h post op
a
Statistically significant.

demonstrated a reduction in pain scores compared with historical con­
trols [43]. However, given a multi-modal intervention was utilised, it is
unclear what specifically contributed to the difference in pain scores and
it remains uncertain whether a similar benefit would be demonstrated if
the intervention was subjected to a randomised controlled trial.
2.2. Pleural fluid drainage or aspiration
Pleural fluid (or air) can be removed from the pleural space either via
an indwelling ICC or using a syringe with needle or cannula (thor­
acocentesis). Thoracocentesis can have diagnostic and/or therapeutic
intent. Removal of either fluid or air can be associated with pain that has
been attributed to rapid changes in pleural pressures [13,44]. Proce­
dural modifications may be able to mitigate these effects, such as the use
of manual drainage (using a syringe) rather than applying continuous
suction via a vacuum bottle [45]. Pharmacological pain control strate­
gies have not been specifically evaluated for this procedure.
2.3. Chemical pleurodesis
Instillation of sclerosant agents into the pleural space is commonly
performed using non-surgical techniques (intrapleural instillation
through an indwelling ICC) [46,47]. Chemical pleurodesis is considered
a definitive procedure in individuals with recurrent pleural effusion or
pneumothorax. Sterile talc is generally considered to be the most
effective sclerosant of the available options with alternative sclerosants
(bleomycin, tetracyclines, silver nitrate, iodopovidone) not shown to
produce better pain control [48–51]. Autologous blood has demon­
strated some promise as an alternative to talc with preliminary studies
demonstrating similar pleurodesis efficacy in malignant pleural effu­
sions but with lower pain scores, however, more research is needed
before this approach can be recommended [52,53]. Intrapleural
administration of local anaesthetic prior to pleurodesis is an appropriate
method to employ to reduce pain during and after pleurodesis. Intra­
pleural lidocaine (250 mg) administered via ICC prior to chemical
pleurodesis was shown to be more effective than a lower dose regimen
[54]. Similar findings have been reported with the use of intrapleural
lidocaine during thoracoscopic pleurodesis [24].
Following pleurodesis, analgesic options can include paracetamol,
opioids and NSAIDs, with evidence from the Therapeutic Intervention in
Malignant Effusion (TIME)-1 study refuting the widely held belief that
NSAID use was associated with lower pleurodesis success [22]. The
choice of oral analgesic regimen therefore can be specifically tailored to
individual patient tolerance and the presence or absence of
contraindications.
Small bore ICCs have been shown to be just as effective as large bore
ICCs in various pleural diseases [55–57]. Small bore ICCs have shown to
cause less pain in pleurodesis [22,58]. The TIME-1 study [22] demon­
strated that mean pain scores (rated on a 0–100 mm VAS) while the ICC
was in situ during pleurodesis were significantly lower in participants
with 12F ICCs compared to participants with 24F ICCs (mean (±SD),
22.0 (±16.6) mm vs. 26.8 (±16.9) mm, p = 0.04). There was no sig­
nificant difference in pleurodesis failure between both groups. Given
small bore tubes cause less pain in comparison to large bore tubes, in
individuals undergoing chemical pleurodesis, small bore ICCs should be
opted over large bore ICCs where possible.
Non-pharmacological measures have been evaluated following
pleurodesis and may provide additional pain control benefits.

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A. Du et al. Respiratory Medicine 207 (2023) 107119

Table 4 routine use [69].

Adverse events from analgesic interventions. Depending on procedure duration and complexity, several regional
Intervention Adverse event Frequency anaesthetic techniques could be considered to avoid the potential risks
of escalating sedation. Multi-level thoracic paravertebral blocks (TPVB)
ICC insertion or removal
Methoxyflurane Cough 35% have been reported to provide analgesic benefit [20,70], with one study
<10F ICC Displacement 18.8% demonstrating superiority to local infiltration of the same dose and type
10–14F ICC Displacement 15.4% of local anaesthetic agents (0.5% bupivacaine and 2% mepivacaine)
Pneumothorax 1.1% [20]. Erector spinae plane blocks with 0.25% bupivacaine or 0.5%
>20F ICC Displacement 9.4%
Empyema 1.9%
ropivacaine have also been explored as the primary anaesthetic,
Pleural drainage demonstrating reductions in additional analgesia with their use [71,72].
Vacuum drainage aspiration Pneumothorax 5.9% Ultrasound-guided mid-transverse process blocks (using a combination
Haemothorax 2% of 0.25% bupivacaine, 2% lidocaine, dexamethasone and clonidine)
Re-expansion pulmonary oedema 2%
have also been reported to produce prolonged pain control both during
Chemical pleurodesis
Intrapleural lidocaine Transient paraesthesia 4% and post medical thoracoscopy [73]. While further comparison studies
NSAIDs vs. Opioids No significant difference in adverse events are required, these anaesthetic techniques are considered to be rela­
12F vs. 24F ICC No significant difference in adverse events tively safe and with appropriate expertise are likely to be useful options.
Autologous venous blood Fever 8.8% .
Sterile talc Fever 28%
Clotted drainage 1.8%
Tetracycline Fever 29.1% 2.5. Pleural biopsy
Medical thoracoscopy
Local anaesthetic infiltration Post-thoracoscopic nausea 6.7% Pleural biopsies involve percutaneous sampling of parietal pleura via
3-level PVB Post-thoracoscopic nausea 10%
a needle through the chest wall [74]. There are different techniques and
2-level PVB Post-thoracoscopic nausea 5.9%
Pneumothorax 5.9% instruments that can be employed and the procedure can be performed
Mini thoracoscope Subcutaneous emphysema 5.6% with or without imaging guidance. There are very few studies available
Post-procedure fever 2.8% assessing analgesic interventions for pleural biopsy. Local infiltration
Semi-rigid thoracoscope Subcutaneous emphysema 10.8% with anaesthetic into the skin, intercostal muscles and pleura is the
Post-procedure fever 2.7%
Incision site infection 2.7%
conventional mode of analgesia, similar to ICC insertion. However, there
Propofol Hypotension 82.2% may be advantages with the use of targeted pleural anaesthesia.
Hypoxaemia 26.7% Administration of local anaesthetic into the extrapleural space, in
Midazolam Hypotension 39.5% addition to conventional skin anaesthesia with 1% lidocaine was shown
Hypoxaemia 3.6%
to be useful in participants undergoing a CT-guided transthoracic needle
Hypoventilation 1.8%
Dexmedetomidine Hypotension 3.3% biopsy [75]. Further studies are required to identify the optimal anal­
gesic regime for these procedures.

Transcutaneous electrical nerve stimulation (TENS) was associated with
a reduction in pain scores for up to 8 h when combined with NSAIDs in
comparison to a control group that received a sham intervention with
the same NSAID regimen [59]. Further studies are required to clarify the
role of this and other non-pharmacological strategies.
2.4. Medical thoracoscopy
Medical thoracoscopy can be performed as a minimally invasive
technique under conscious sedation with local anaesthesia and allows
both diagnostic (e.g. pleural biopsy) and therapeutic interventions (e.g.
drainage, adhesiolysis, pleurodesis) to be performed in people that are
not safe for general anaesthesia [60,61]. Procedural differences are a
key factor in the adequacy of pain control during medical thoracoscopy.
Rigid instruments are associated with more procedural pain than
flexi-rigid instruments [62]. This is thought to relate to the need for
greater manipulation of the instrument during the procedure to access
target sites [63]. A balance between procedural proficiency and pain
control must always be sought, but it is likely that longer procedures
performed with rigid instruments may benefit from long-acting regional
anaesthesia with an effect that will persist beyond the procedure time.
Pharmacological approaches for conscious sedation vary but com­
binations of sedatives with analgesic agents predominate. Fentanyl with
midazolam represents a relatively standard approach, although the
substitution of midazolam with dexmedetomidine or the addition of
dexmedetomidine are strategies that have both been suggested to be
beneficial [64–67]. Despite its side-effect profile, propofol is preferred
by some, and has been reported to require less breakthrough analgesia in
at least one study [21]. Combining intravenous sedatives with intra­
pleural local anaesthetic (lidocaine) was initially thought to provide
durable pain control [68], but has since been shown to lack clinically
meaningful reductions in pain scores, therefore is not recommended for
3. Future research
Given the limitations of pre-existing studies and the diverse experi­
ence of pain in pleural procedures, there is still yet to be a standardised
approach to pain management in non-surgical pleural procedures.
Current literature is limited by heterogeneity in study design and
outcome measures, making comparability between study findings
difficult. Further research should be targeted at building evidence on the
effective modes of analgesia identified in this review and employing
them across larger and more consistent sample sizes and across various
pleural procedures. More importantly, pain should be the primary
outcome assessed, with a consensus on endpoints and the optimal tool to
measure pain. Ultimately, future research should help to reduce het­
erogeneity in approach and provide clarity to clinicians allowing them
to employ the most consistently effective approach across most care
settings where non-surgical pleural procedures are performed.
4. Conclusions
Pain during non-surgical pleural procedures remains a significant
impediment to their successful completion and patients are likely to
benefit from a more uniform approach to care. Improvements in pleural
procedural pain control have been associated with higher rates of pos­
itive patient experience, mobility, and greater willingness to repeat the
procedure if clinically indicated [17,76]. Current evidence supports the
use of longer acting local intrapleural anaesthetics in ICC insertion.
Small-bore ICCs should generally be chosen over large-bore ICCs where
possible. Paravertebral blocks with long-acting local anaesthetics for
prolonged procedures or those where larger or more rigid instruments
are used should also improve pain outcomes. No clear advantage has
been demonstrated in any anaesthetic strategy for chemical pleurodesis
apart from pre-treatment with local anaesthetic via the ICC. The choice

9
A. Du et al. Respiratory Medicine 207 (2023) 107119

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